5-fluoro pyrimidine derivatives

ABSTRACT

This present disclosure is related to the field of 5-fluoro pyrimidines and their derivatives and to the use of these compounds as fungicides.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S. patent application Ser. No. 12/357,710, filed Jan. 22, 2009, which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/011,799 filed Jan. 22, 2008, and U.S. Provisional Patent Application Ser. No. 61/115,297 filed Nov. 17, 2008.

FIELD OF THE INVENTION

This present disclosure is related to the field of 5-fluoro pyrimidines and their derivatives and to the use of these compounds as fungicides.

BACKGROUND AND SUMMARY OF THE INVENTION

Fungicides are compounds, of natural or synthetic origin, which act to protect and cure plants against damage caused by agriculturally relevant fungi. Generally, no single fungicide is useful in all situations. Consequently, research is ongoing to produce fungicides that may have better performance, are easier to use, and cost less.

The present disclosure relates to 5-fluoro pyrimidine compounds and their use as fungicides. The compounds of the present disclosure may offer protection against ascomycetes, basidiomycetes, deuteromycetes and oomycetes.

One embodiment of the present disclosure may include compounds of Formula I:

wherein R¹ is —N(R³)R⁴;

R² is —OR²¹; R³ is:

-   -   H;     -   C₁-C₆ alkyl optionally substituted with 1- to 3 R⁵;     -   C₂-C₆ alkenyl optionally substituted with 1-3 R⁵;     -   a 5- or 6-membered heteroaromatic ring selected from the group         consisting of furanyl, pyridinyl, pyridinyl-N-oxide,         pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, triazinyl,         thiadiazolyl, oxazolyl, isoxazolyl, triazolyl, each         heteroaromatic ring being optionally substituted with 1-3 R³⁰;     -   imidazole fused with an aromatic or heteroaromatic ring selected         from the group consisting of benzene, oxazole, isoxazole, furan,         thiazole, pyrimidine, pyridine, pyrrole, pyrazine, thiophene,         each aromatic or heteroaromatic ring being optionally         substituted with 1 to 3 R³⁰;     -   benzo[1,3]dioxolyl;     -   3H-isobenzofuran-1-onyl;     -   cyano;     -   C₃-C₆ alkynyl optionally substituted with 1-3 R⁵;     -   —C(═O)R⁶;     -   —C(═O)OCH₂C(═O)R⁸;     -   —C(═S)R⁶;     -   —C(═S)NHR⁸;     -   —C(═O)N(R⁸)R¹⁰;     -   —OR⁷;     -   —P(O)(OR¹⁵)₂;     -   —S(O)₂R⁸;     -   —SR⁸;     -   —Si(R⁸)₃;     -   —N(R⁹)R¹⁰;     -   —N═C(R¹⁵)R¹⁶;     -   —(CHR²²)_(m)R³⁷;     -   —(CHR²⁴)OR²⁹;     -   —C(═NR¹⁶)SR¹⁶; or     -   —C(═NR²⁷)NR¹³R²⁸;         wherein m is an integer from 1-3;

R⁴ is:

-   -   H;     -   hydroxyl;     -   amino;     -   C₁-C₆ alkyl, optionally substituted with 1-3 R⁵;     -   —C(═O)R⁶; or     -   —C(═O)N(R⁸)R¹⁰);         alternatively R³ and R⁴ may be taken together to form:     -   a 5- or 6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹;     -   ═C(R¹²)N(R¹³)R¹⁴;     -   ═C(R¹³)(R¹⁴);     -   ═C(R¹⁵)OR¹⁵;     -   ═S(R³⁴)₂; or     -   ═NR³⁵;         R⁵ is independently halogen, C₁-C₆ alkyl, C₁-C₄ haloalkyl, C₁-C₄         alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ haloalkylthio,         amino, C₁-C₃ alkylamino, C₂-C₆ alkoxycarbonyl, C₂-C₆         alkylcarbonyl, C₂-C₆ alkylaminocarbonyl, —OH, N-methyl         piperazine or C₃-C₆ trialkylsilyl;         R⁶ is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl optionally         substituted with 1-3 R³⁰, C₁-C₅ haloalkyl, C₁-C₅ alkoxy, C₁-C₅         haloalkoxy C₂-C₆ alkoxycarbonyl, C₁-C₄ alkoxyalkoxy, C₂-C₆         alkylaminocarbonyl; 1-benzo[1,2,3]thiadiazol-7-yl, thiazolyl,         benzyl, phenyl, phenoxy, or benzyloxy wherein the thiazolyl,         benzyl, phenyl, phenoxy, or benzyloxy may be optionally         substituted with 1-3 R²⁰, a 5- or 6-membered saturated or         unsaturated ring containing 1-3 heteroatoms wherein each ring         may be optionally substituted with 1-3 R¹¹;         R⁷ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₅ haloalkyl, benzyl         which may be optionally substituted with 1-5 R²⁰,         —CHR¹⁸C(O)OR¹⁹, —(CHR²⁷)R²⁸, —Si(R⁸)₃, or a 5- or 6-membered         saturated or unsaturated ring containing 1-3 heteroatoms wherein         each ring may be optionally substituted with 1-3 R¹¹;         R⁸ is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, amino, C₁-C₆         alkylamino, C₂-C₆ dialkylamino, methylene-2-furanyl,         —CHR¹⁵C(O)OR¹⁹, benzyl optionally substituted with 1-3 R³⁰,         phenyl optionally substituted with 1-3 R³⁰, or a 5- or         6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹;         R⁹ is H, C₁-C₆ alkyl C₁-C₆ haloalkyl, —C(═O)R¹⁷, benzothiazoyl,         quinazolinyl, or phenyl optionally substituted with 1-3 R²⁰, a         5- or 6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹;         R¹⁰ is H or C₁-C₆ alkyl, C₁-C₆ haloalkyl, or phenyl optionally         substituted with 1-3 R²⁰;         R¹¹ is independently halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl,         C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆         haloalkylthio, amino, C₁-C₆ alkylamino, C₂-C₆ dialkylamino,         C₂-C₆ alkoxycarbonyl, or C₂-C₆ alkylcarbonyl;         R¹² is H or C₁-C₄ alkyl;         R¹³ and R¹⁴ are independently H, cyano, —OH, C₁-C₄ alkyl, C₁-C₆         alkoxy, C₂-C₆, alkylcarbonyl, phenyl, or benzyl wherein the         phenyl or benzyl may be optionally substituted with 1-3 R²⁰;         alternatively R¹³ and R¹⁴ may be taken together to form:     -   a 5- or 6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹, or 3,4-dihydro-1H-isoquinolin-2-yl;         alternatively R¹² and R¹³ may be taken together to form:     -   a 5- or 6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹;         R¹⁵ is H or C₁-C₆ alkyl, C₂-C₆ alkenyl, 2-benzofuranyl, a 5- or         6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹;         R¹⁶ is H, C₁-C₆ alkyl, or phenyl optionally substituted with 1-3         R²⁰;         alternatively R¹⁵ and R¹⁶ may be taken together as —(CH₂)₄— or         —(CH₂)₅—;         R¹⁷ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₁-C₆         alkoxy, benzyl, phenyl, phenoxy, or benzyloxy wherein each ring         may be optionally substituted with 1-3 R²⁰, a 5- or 6-membered         saturated or unsaturated ring containing 1-3 heteroatoms wherein         each ring may be optionally substituted with 1-3 R¹¹;         R¹⁸ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;         R¹⁹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or benzyl;         R²⁰ is independently halogen, cyano, nitro, amino, C₁-C₆         alkoxyalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl,         C₂-C₆ alkoxyalkyl, C₂-C₆ haloalkoxyalkyl, C₂-C₆ alkenyl, C₂-C₆         haloalkenyl, C₃-C₆ alkynyl, C₃-C₆ haloalkynyl, hydroxyl, C₁-C₆         alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyloxy, C₂-C₆         haloalkenyloxy, C₃-C₆ alkynyloxy, C₃-C₆ haloalkynyloxy, C₁-C₆         alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆         haloalkylsulfonyl, C₂-C₆ alkenylthio, C₂-C₆ haloalkenylthio,         C₂-C₆ haloalkenylsulfonyl, C₃-C₆ alkynylthio, C₃-C₆         alkynylsulfonyl, C₃-C₆ haloalkynylsulfonyl, C₁-C₆ alkylamino,         C₂-C₈ dialkylamino, C₃-C₈ dialkylaminocarbonyl, C₂-C₆         alkoxycarbonyl, C₂-C₆ alkylcarbonyl, C₃-C₆ trialkylsilyl,         2-[(E)-methoxyimino]-N-methyl-acetamidyl, phenyl, benzyl,         benzyloxy, phenoxy, or a 5- or 6-membered heteroaromatic ring         wherein each phenyl, benzyl, benzyloxy, phenoxy, or 5- or         6-membered heteroaromatic ring may be optionally substituted         with 1-3 substitutents independently selected from R³¹;

R²¹ is:

-   -   H;     -   C₁-C₁₄ alkyl;     -   C₁-C₆ haloalkyl;     -   C₂-C₄ alkenyl;     -   C₂-C₄ haloalkenyl;     -   C₃-C₄ alkynyl;     -   C₃-C₄ haloalkynyl;     -   phenyl, naphthyl, or tetrahydroquinolinyl each optionally         substituted with 1-3 R²⁰;     -   —(CHR²²)_(m)R²³;     -   —(CHR²⁴)_(m)C(O)OR²⁵;     -   —(CHR²⁴)_(m)C(O)R²⁶;     -   —(CHR²⁴)_(m)C(O)N(R²⁷)R²⁸;     -   —(CHR²⁴)_(m)OR²⁹;     -   —(CHR²⁴)_(m)SR²⁹     -   —(CHR²⁴)_(m)N(R²⁷)R²⁸;     -   —C(═O)R³²;     -   —N═C(R³²)(R³⁶);     -   —NR²⁵C(═O)OR²⁵     -   —Si(R⁸)₃;     -   —SO₂R³³;     -   C₂-C₆ alkoxy carbonyl;     -   C₂-C₆ alkylaminocarbonyl;     -   C₂-C₆ alkylcarbonyl;     -   sugars selected from the group consisting of         beta-D-glucose-tetraacetate, rhamnose, fructose, and pentose; or     -   a 5- or 6-membered heteroaromatic ring selected from the group         consisting of furanyl, pyridinyl, pyridinyl-N-oxide,         pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl,         triazinyl, thiadiazolyl, oxazolyl, triazolyl or isoxazolyl         wherein each 5- or 6-member heteroaromatic ring may be         optionally substituted with 1-5 R²⁰;         R²² is independently:     -   H;     -   halogen;     -   cyano;     -   nitro;     -   C₁-C₆ alkyl;     -   C₁-C₆ haloalkyl;     -   phenyl or benzyl optionally substituted with 1-3 R²⁰;     -   C₁-C₆ hydroxyalkyl;     -   C₂-C₆ alkoxylalkyl;     -   C₃-C₆ haloalkynyl;     -   C₂-C₆ alkenyl;     -   C₂-C₆ haloalkenyl;     -   C₃-C₆ alkynyl;     -   C₁-C₆ alkoxy;     -   C₁-C₆ haloalkoxy;     -   C₁-C₆ alkylthio;     -   C₁-C₆ alkylamino;     -   C₂-C₈ dialkylamino;     -   C₃-C₆ cycloalkylamino;     -   C₄-C₆ (alkyl)cycloalkylamino;     -   C₂-C₆ alkylcarbonyl;     -   C₂-C₆ alkoxycarbonyl;     -   C₂-C₆ alkylaminocarbonyl;     -   C₃-C₈ dialkylaminocarbonyl;     -   C₃-C₆ trialkylsilyl;     -   ring-fused heteroaromatic rings selected from the group         consisting of benzothiophenyl, quinolinyl, isoquinolinyl,         thieno[2,3-b]pyridyl, 1-methyl-1H-thieno[2,3-c]pyrazolyl, and         benzoimidazolyl, wherein each of the rings may be further         substituted with 1-3 R²⁰; or     -   a 5- or 6-membered heteroaromatic ring selected from the group         consisting of furanyl, pyridinyl, pyridinyl-N-oxide,         pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, triazinyl,         thiadiazolyl, oxazolyl, isoxazolyl, triazolyl and thienyl;

R²³ is:

-   -   H;     -   halogen;     -   C₁-C₆ alkyl;     -   C₁-C₆ haloalkyl;     -   C₂-C₆ dialkylamino;     -   phenyl optionally substituted with 1-5 R²⁰;     -   ring-fused heteroaromatic rings selected from the group         consisting of benzothiophenyl, quinolinyl, isoquinolinyl,         thieno[2,3-b]pyridyl, 1-methyl-1H-thieno[2,3-c]pyrazolyl,         benzofuranyl and benzoimidazolyl, 2,3-dihydrobenzofuran-2-yl,         4-methyl-4H-thieno[3,2-b]pyrrol-5-yl, 1-methyl-1H-indol-5-yl,         imidazo[1,2-a]pyridin-2-yl, imidazo[2,1-b]thiazol-6-yl,         benzothiazol-2-yl, benzo[b]thiophen-7-yl, and         1-methyl-1H-indazol-3-yl, wherein each of the rings may be         further substituted with 1-3 R²⁰;     -   naphthyl;     -   benzo[1,3]dioxolyl;     -   pyrrolidinonyl;     -   oxetanyl;     -   C₁-C₆ alkylthio optionally substituted with 1-5 R²⁰;     -   a 5- or 6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹; or     -   a 5- or 6-membered heteroaromatic ring selected from the group         consisting of furanyl, pyridinyl, pyridinyl-N-oxide,         pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl,         triazinyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl,         imidazolyl, thiophene-2-yl and thiophen-3-yl wherein each         heteroaromatic ring may be optionally substituted with 1-3 R²⁰;         R²⁴ is H, C₁-C₆ alkyl, C₁-C₆ alkoxy, benzyl, or phenyl wherein         each of the benzyl or phenyl may be optionally substituted with         1-3 R²⁰;         R²⁵ is H, C₁-C₆ alkyl, phenyl or benzyl optionally substituted         with 1-3 R²⁰;

R²⁶ is:

-   -   H;     -   C₁-C₆ alkyl;     -   C₁-C₆ alkoxy;     -   phenyl optionally substituted with 1-3 R²⁰; or     -   a 5- or 6 membered heteroaromatic ring selected from the group         consisting of furanyl, pyridinyl, pyridinyl-N-oxide,         pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, triazinyl,         thiadiazolyl, oxazolyl, triazolyl and isoxazolyl;         R²⁷ and R²⁸ are independently:     -   H;     -   C₁-C₆ alkyl;     -   benzyl or phenyl wherein each of the benzyl or phenyl may be         optionally substituted with 1-3 R²⁰; or     -   a 5- or 6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹;

R²⁹ is:

-   -   H;     -   C₁-C₆ alkyl;     -   C₁-C₆ haloalkyl;     -   C₁-C₆ alkoxyalkyl;     -   C₂-C₆ alkylcarbonyl;     -   benzyl, benzoyl, or phenyl wherein each of the benzyl, benzoyl         or phenyl may be optionally substituted with 1-3 R²⁰; or     -   a 5- or 6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹;         R³⁰ is independently halogen, cyano, nitro, C₁-C₆ alkyl, C₁-C₆         haloalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkoxyalkyl, C₂-C₆         haloalkoxyalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₃-C₆         alkynyl, C₃-C₆ haloalkynyl, hydroxyl, C₁-C₆ alkoxy, C₁-C₆         haloalkoxy, C₂-C₆ alkenyloxy, C₂-C₆ haloalkenyloxy, C₃-C₆         alkynyloxy, C₃-C₆ haloalkynyloxy, C₁-C₆ alkylthio, C₁-C₆         alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₂-C₆ alkenylthio, C₂-C₆         haloalkenylthio, C₂-C₆ haloalkenylsulfonyl, C₃-C₆ alkynylthio,         C₃-C₆ alkynylsulfonyl, C₃-C₆ haloalkynylsulfonyl, C₁-C₆         alkylamino, C₂-C₈ dialkylamino, C₃-C₈ dialkylaminocarbonyl,         C₃-C₆ trialkylsilyl, thiazolyl, phenyl, pyrimidinyl, or pyridyl,         wherein the thiazolyl, phenyl, pyridyl, or pyrimidinyl may be         optionally substituted with 1-3 R²⁰;         R³¹ is independently halogen, cyano, nitro, C₁-C₆ alkyl, C₁-C₆         haloalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkoxyalkyl, C₂-C₆         haloalkoxyalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₃-C₆         alkynyl, C₃-C₆ haloalkynyl, hydroxyl, C₁-C₆ alkoxy, C₁-C₆         haloalkoxy, C₂-C₆ alkenyloxy, C₂-C₆ haloalkenyloxy, C₃-C₆         alkynyloxy, C₃-C₆ haloalkynyloxy, C₁-C₆ alkylthio, C₁-C₆         alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₂-C₆ alkenylthio, C₂-C₆         haloalkenylthio, C₂-C₆ haloalkenylsulfonyl, C₃-C₆ alkynylthio,         C₃-C₆ alkynylsulfonyl, C₃-C₆ haloalkynylsulfonyl, C₁-C₆         alkylamino, C₂-C₈ dialkylamino, C₃-C₈ dialkylaminocarbonyl, or         C₃-C₆ trialkylsilyl;         R³² is independently:     -   C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆         alkoxyalkyl, C₂-C₆ haloalkoxyalkyl, C₂-C₆ alkenyl, C₂-C₆         haloalkenyl, C₃-C₆ alkynyl, C₃-C₆ haloalkynyl, hydroxyl, C₁-C₆         alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyloxy, C₂-C₆         haloalkenyloxy, C₃-C₆ alkynyloxy, C₃-C₆ haloalkynyloxy, C₁-C₆         alkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₂-C₆         alkenylthio, C₂-C₆ haloalkenylthio, C₂-C₆ haloalkenylsulfonyl,         C₃-C₆ alkynylthio, C₃-C₆ alkynylsulfonyl, C₃-C₆         haloalkynylsulfonyl, C₁-C₆ alkylamino, C₂-C₈ dialkylamino, C₃-C₈         dialkylaminocarbonyl, C₃-C₆ trialkylsilyl;     -   phenyl wherein the phenyl ring may be optionally substituted         with 1-3 R²⁰; or     -   a 5- or 6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹;         R³³ is independently:     -   C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl or thienyl optionally         substituted with 1-3 R²⁰; or     -   a 5- or 6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹;

R³⁴ is:

-   -   C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkoxyalkyl, C₁-C₆         alkylamino; or     -   a 5- or 6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹;

R³⁵ is:

-   -   C₁-C₆ alkyl, C₂-C₆ alkylcarbonyl; or     -   a 5- or 6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹;         R³⁶ is H, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy, benzyl, or phenyl         wherein each of the benzyl, or phenyl may be optionally         substituted with 1-3 R²⁰;         alternatively R³² and R³⁶ may be taken together to form:     -   a 5- or 6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹; and         R³⁷ is independently:     -   H, halogen, or phenyl optionally substituted with 1-5 R²⁰;     -   C₁-C₆ alkyl, C₁-C₆ haloalkyl, hydroxyl, C₁-C₆ alkoxy, or C₁-C₆         haloalkoxy; or     -   a 5- or 6-membered saturated or unsaturated ring containing 1-3         heteroatoms wherein each ring may be optionally substituted with         1-3 R¹¹.

Another embodiment of the present disclosure may include a fungicidal composition for the control or prevention of fungal attack comprising the compounds described above and a phytologically acceptable carrier material.

Yet another embodiment of the present disclosure may include a method for the control or prevention of fungal attack on a plant, the method including the steps of applying a fungicidally effective amount of one or more of the compounds described above to at least one of the fungus, the plant, an area adjacent to the plant, and the seed adapted to produce the plant.

The term “alkyl” refers to an unbranched, branched, or cyclic carbon chain, including methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term “alkenyl” refers to a branched, unbranched or cyclic carbon chain containing one or more double bonds including ethenyl, propenyl, butenyl, isopropenyl, isobutenyl, cyclohexenyl, and the like.

The term “alkynyl” refers to refers to a branched or unbranched carbon chain containing one or more triple bonds including propynyl, butynyl and the like.

As used throughout this specification, the term ‘R’ refers to the group consisting of C₂₋₈ alkyl, C₃₋₈ alkenyl or C₃₋₈ alkynyl, unless stated otherwise.

The term “alkoxy” refers to an —OR substituent.

The term “alkoxycarbonyl” refers to a —C(O)—OR substituent.

The term “alkylcarbonyl” refers to a —C(O)—R substituent.

The term “alkylsulfonyl” refers to an —SO₂—R substituent.

The term “haloalkylsulfonyl” refers to a sulfonyl substitution on an alkyl which is partially substituted with halogen atoms.

The term “alkylthio” refers to an —S—R substituent.

The term “alkylaminocarbonyl” refers to a —C(O)—N(H)—R substituent.

The term “dialkylaminocarbonyl” refers to a —C(O)—NR₂ substituent.

The term “alkylcycloalkylamino” refers to a cycloalkylamino substituent that is substituted with an alkyl group.

The term “trialkylsilyl” refers to —SiR₃.

The term “cyano” refers to a —C≡N substituent.

The term “hydroxyl” refers to a —OH substituent

The term “amino” refers to a —NH₂ substituent

The term “alkylamino” refers to a —N(H)—R substituent

The term “dialkylamino” refers to a —NR₂ substituent

The term “alkoxyalkoxy” refers to —O(CH₂)_(n)O(CH₂)_(n) where n is an integer from 1-3

The term “alkoxyalkyl” refers to an alkoxy substitution on an alkyl.

The term “haloalkoxyalkyl” refers to an alkoxy substitution on an alkyl which may be partially substituted with halogen atoms

The term “hydroxyalkyl” refers to an alkyl which is substituted with a hydroxyl group.

The term “haloalkoxy” refers to a —OR—X substituent, wherein X is Cl, F, Br, or I, or any combination thereof.

The term “haloalkyl” refers to an alkyl, which is substituted with Cl, F, I, or Br or any combination thereof.

The term “haloalkenyl” refers to an alkenyl, which is substituted with Cl, F, I, or Br or any combination thereof.

The term “haloalkynyl” refers to an alkynyl which is substituted with Cl, F, I, or Br or any combination thereof.

The term “halogen” or “halo” refers to one or more halogen atoms, defined as F, Cl, Br, and I.

The term “hydroxycarbonyl” refers to a —C(O)—OH substituent.

The term “nitro” refers to a —NO₂ substituent.

The term “thienyl” refers to a 5-member aromatic ring with one sulfur atom.

Throughout the disclosure, reference to the compounds of Formula I is read as also including optical isomers and salts of Formula I, and hydrates thereof. Specifically, when Formula I contains a branched chain alkyl group, it is understood that such compounds include optical isomers and racemates thereof. Exemplary salts include: hydrochloride, hydrobromide, hydroiodide, and the like.

It is also understood by those skilled in the art that additional substitution is allowable, unless otherwise noted, as long as the rules of chemical bonding and strain energy are satisfied and the product still exhibits fungicidal activity.

Another embodiment of the present disclosure is a use of a compound of Formula I, for protection of a plant against attack by a phytopathogenic organism or the treatment of a plant infested by a phytopathogenic organism, comprising the application of a compound of Formula I, or a composition comprising the compound to soil, a plant, a part of a plant, foliage, and/or seeds.

Additionally, another embodiment of the present disclosure is a composition useful for protecting a plant against attack by a phytopathogenic organism and/or treatment of a plant infested by a phytopathogenic organism comprising a compound of Formula I and a phytologically acceptable carrier material.

DETAILED DESCRIPTION OF THE PRESENT DISCLOSURE

The compounds of the present disclosure may be applied by any of a variety of known techniques, either as the compounds or as formulations comprising the compounds. For example, the compounds may be applied to the roots, seeds or foliage of plants for the control of various fungi, without damaging the commercial value of the plants. The materials may be applied in the form of any of the generally used formulation types, for example, as solutions, dusts, wettable powders, flowable concentrates, or emulsifiable concentrates.

Preferably, the compounds of the present disclosure are applied in the form of a formulation, comprising one or more of the compounds of Formula I with a phytologically acceptable carrier. Concentrated formulations may be dispersed in water, or other liquids, for application, or formulations may be dust-like or granular, which may then be applied without further treatment. The formulations can be prepared according to procedures that are conventional in the agricultural chemical art.

The present disclosure contemplates all vehicles by which one or more of the compounds may be formulated for delivery and use as a fungicide. Typically, formulations are applied as aqueous suspensions or emulsions. Such suspensions or emulsions may be produced from water-soluble, water suspendable, or emulsifiable formulations which are solids, usually known as wettable powders; or liquids, usually known as emulsifiable concentrates, aqueous suspensions, or suspension concentrates. As will be readily appreciated, any material to which these compounds may be added may be used, provided it yields the desired utility without significant interference with the activity of these compounds as antifungal agents.

Wettable powders, which may be compacted to form water dispersible granules, comprise an intimate mixture of one or more of the compounds of Formula I, an inert carrier and surfactants. The concentration of the compound in the wettable powder may be from about 10 percent to about 90 percent by weight based on the total weight of the wettable powder, more preferably about 25 weight percent to about 75 weight percent. In the preparation of wettable powder formulations, the compounds may be compounded with any finely divided solid, such as prophyllite, talc, chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein, gluten, montmorillonite clays, diatomaceous earths, purified silicates or the like. In such operations, the finely divided carrier and surfactants are typically blended with the compound(s) and milled

Emulsifiable concentrates of the compounds of Formula I may comprise a convenient concentration, such as from about 10 weight percent to about 50 weight percent of the compound, in a suitable liquid, based on the total weight of the concentrate. The compounds may be dissolved in an inert carrier, which is either a water miscible solvent or a mixture of water-immiscible organic solvents, and emulsifiers. The concentrates may be diluted with water and oil to form spray mixtures in the form of oil-in-water emulsions. Useful organic solvents include aromatics, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, for example, terpenic solvents, including rosin derivatives, aliphatic ketones, such as cyclohexanone, and complex alcohols, such as 2-ethoxyethanol.

Emulsifiers which may be advantageously employed herein may be readily determined by those skilled in the art and include various nonionic, anionic, cationic and amphoteric emulsifiers, or a blend of two or more emulsifiers. Examples of nonionic emulsifiers useful in preparing the emulsifiable concentrates include the polyalkylene glycol ethers and condensation products of alkyl and aryl phenols, aliphatic alcohols, aliphatic amines or fatty acids with ethylene oxide, propylene oxides such as the ethoxylated alkyl phenols and carboxylic esters solubilized with the polyol or polyoxyalkylene. Cationic emulsifiers include quaternary ammonium compounds and fatty amine salts. Anionic emulsifiers include the oil-soluble salts (e.g., calcium) of alkylaryl sulphonic acids, oil soluble salts or sulfated polyglycol ethers and appropriate salts of phosphated polyglycol ether.

Representative organic liquids which may be employed in preparing the emulsifiable concentrates of the compounds of the present invention are the aromatic liquids such as xylene, propyl benzene fractions; or mixed naphthalene fractions, mineral oils, substituted aromatic organic liquids such as dioctyl phthalate; kerosene; dialkyl amides of various fatty acids, particularly the dimethyl amides of fatty glycols and glycol derivatives such as the n-butyl ether, ethyl ether or methyl ether of diethylene glycol, and the methyl ether of triethylene glycol and the like. Mixtures of two or more organic liquids may also be employed in the preparation of the emulsifiable concentrate. Organic liquids include xylene, and propyl benzene fractions, with xylene being most preferred in some cases. Surface-active dispersing agents are typically employed in liquid formulations and in an amount of from 0.1 to 20 percent by weight based on the combined weight of the dispersing agent with one or more of the compounds. The formulations can also contain other compatible additives, for example, plant growth regulators and other biologically active compounds used in agriculture.

Aqueous suspensions comprise suspensions of one or more water-insoluble compounds of Formula I, dispersed in an aqueous vehicle at a concentration in the range from about 5 to about 50 weight percent, based on the total weight of the aqueous suspension. Suspensions are prepared by finely grinding one or more of the compounds, and vigorously mixing the ground material into a vehicle comprised of water and surfactants chosen from the same types discussed above. Other components, such as inorganic salts and synthetic or natural gums, may also be added to increase the density and viscosity of the aqueous vehicle.

The compounds of Formula I can also be applied as granular formulations, which are particularly useful for applications to the soil. Granular formulations generally contain from about 0.5 to about 10 weight percent, based on the total weight of the granular formulation of the compound(s), dispersed in an inert carrier which consists entirely or in large part of coarsely divided inert material such as attapulgite, bentonite, diatomite, clay or a similar inexpensive substance. Such formulations are usually prepared by dissolving the compounds in a suitable solvent and applying it to a granular carrier which has been preformed to the appropriate particle size, in the range of from about 0.5 to about 3 mm A suitable solvent is a solvent in which the compound is substantially or completely soluble. Such formulations may also be prepared by making a dough or paste of the carrier and the compound and solvent, and crushing and drying to obtain the desired granular particle.

Dusts containing the compounds of Formula I may be prepared by intimately mixing one or more of the compounds in powdered form with a suitable dusty agricultural carrier, such as, for example, kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1 to about 10 weight percent of the compounds, based on the total weight of the dust.

The formulations may additionally contain adjuvant surfactants to enhance deposition, wetting and penetration of the compounds onto the target crop and organism. These adjuvant surfactants may optionally be employed as a component of the formulation or as a tank mix. The amount of adjuvant surfactant will typically vary from 0.01 to 1.0 percent by volume, based on a spray-volume of water, preferably 0.05 to 0.5 volume percent. Suitable adjuvant surfactants include, but are not limited to ethoxylated nonyl phenols, ethoxylated synthetic or natural alcohols, salts of the esters or sulphosuccinic acids, ethoxylated organosilicones, ethoxylated fatty amines and blends of surfactants with mineral or vegetable oils. The formulations may also include oil-in-water emulsions such as those disclosed in U.S. patent application Ser. No. 11/495,228, the disclosure of which is expressly incorporated by reference herein.

The formulations may optionally include combinations that contain other pesticidal compounds. Such additional pesticidal compounds may be fungicides, insecticides, herbicides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the compounds of the present invention in the medium selected for application, and not antagonistic to the activity of the present compounds. Accordingly, in such embodiments, the other pesticidal compound is employed as a supplemental toxicant for the same or for a different pesticidal use. The compounds of Formula I, and the pesticidal compound in the combination can generally be present in a weight ratio of from 1:100 to 100:1.

The compounds of the present disclosure may also be combined with other fungicides to form fungicidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure are often applied in conjunction with one or more other fungicides to control a wider variety of undesirable diseases. When used in conjunction with other fungicide(s), the presently claimed compounds may be formulated with the other fungicide(s), tank mixed with the other fungicide(s) or applied sequentially with the other fungicide(s). Such other fungicides may include 2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol, 8-hydroxyquinoline sulfate, ametoctradin, amisulbrom, antimycin, Ampelomyces quisqualis, azaconazole, azoxystrobin, Bacillus subtilis, benalaxyl, benomyl, benthiavalicarb-isopropyl, benzylaminobenzene-sulfonate (BABS) salt, bicarbonates, biphenyl, bismerthiazol, bitertanol, bixafen, blasticidin-S, borax, Bordeaux mixture, boscalid, bromuconazole, bupirimate, calcium polysulfide, captafol, captan, carbendazim, carboxin, carpropamid, carvone, chloroneb, chlorothalonil, chlozolinate, Coniothyrium minitans, copper hydroxide, copper octanoate, copper oxychloride, copper sulfate, copper sulfate (tribasic), cuprous oxide, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, dazomet, debacarb, diammonium ethylenebis-(dithiocarbamate), dichlofluanid, dichlorophen, diclocymet, diclomezine, dichloran, diethofencarb, difenoconazole, difenzoquat ion, diflumetorim, dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinobuton, dinocap, diphenylamine, dithianon, dodemorph, dodemorph acetate, dodine, dodine free base, edifenphos, enestrobin, epoxiconazole, ethaboxam, ethoxyquin, etridiazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fentin, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumorph, fluopicolide, fluopyram, fluoroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutianil, flutolanil, flutriafol, folpet, formaldehyde, fosetyl, fosetyl-aluminium, fuberidazole, furalaxyl, furametpyr, guazatine, guazatine acetates, GY-81, hexachlorobenzene, hexaconazole, hymexazol, imazalil, imazalil sulfate, imibenconazole, iminoctadine, iminoctadine triacetate, iminoctadine tris(albesilate), ipconazole, iprobenfos, iprodione, iprovalicarb, isoprothiolane, isopyrazam, isotianil, kasugamycin, kasugamycin hydrochloride hydrate, kresoxim-methyl, mancopper, mancozeb, mandipropamid, maneb, mepanipyrim, mepronil, mercuric chloride, mercuric oxide, mercurous chloride, metalaxyl, mefenoxam, metalaxyl-M, metam, metam-ammonium, metam-potassium, metam-sodium, metconazole, methasulfocarb, methyl iodide, methyl isothiocyanate, metiram, metominostrobin, metrafenone, mildiomycin, myclobutanil, nabam, nitrothal-isopropyl, nuarimol, octhilinone, ofurace, oleic acid (fatty acids), orysastrobin, oxadixyl, oxine-copper, oxpoconazole fumarate, oxycarboxin, pefurazoate, penconazole, pencycuron, penflufen, pentachlorophenol, pentachlorophenyl laurate, penthiopyrad, phenylmercury acetate, phosphonic acid, phthalide, picoxystrobin, polyoxin B, polyoxins, polyoxorim, potassium bicarbonate, potassium hydroxyquinoline sulfate, probenazole, prochloraz, procymidone, propamocarb, propamocarb hydrochloride, propiconazole, propineb, proquinazid, prothioconazole, pyraclostrobin, pyrametostrobin, pyraoxystrobin, pyrazophos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyroquilon, quinoclamine, quinoxyfen, quintozene, Reynoutria sachalinensis extract, sedaxane, silthiofam, simeconazole, sodium 2-phenylphenoxide, sodium bicarbonate, sodium pentachlorophenoxide, spiroxamine, sulfur, SYP-Z071, SYP-Z048, tar oils, tebuconazole, tebufloquin, tecnazene, tetraconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triazoxide, tricyclazole, tridemorph, trifloxystrobin, triflumizole, triforine, triticonazole, validamycin, valifenalate, valiphenal, vinclozolin, zineb, ziram, zoxamide, Candida oleophila, Fusarium oxysporum, Gliocladium spp., Phlebiopsis gigantea, Streptomyces griseoviridis, Trichoderma spp., (RS)—N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide, 1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate, 1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane, 2-(2-heptadecyl-2-imidazolin-1-yl)ethanol, 2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide, 2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride, 2-methoxyethylmercury silicate, 3-(4-chlorophenyl)-5-methylrhodanine, 4-(2-nitroprop-1-enyl)phenyl thiocyanateme, ampropylfos, anilazine, azithiram, barium polysulfide, Bayer 32394, benodanil, benquinox, bentaluron, benzamacril; benzamacril-isobutyl, benzamorf, binapacryl, bis(methylmercury) sulfate, bis(tributyltin) oxide, buthiobate, cadmium calcium copper zinc chromate sulfate, carbamorph, CECA, chlobenthiazone, chloraniformethan, chlorfenazole, chlorquinox, climbazole, copper bis(3-phenylsalicylate), copper zinc chromate, cufraneb, cupric hydrazinium sulfate, cuprobam, cyclafuramid, cypendazole, cyprofuram, decafentin, dichlone, dichlozoline, diclobutrazol, dimethirimol, dinocton, dinosulfon, dinoterbon, dipyrithione, ditalimfos, dodicin, drazoxolon, EBP, ESBP, etaconazole, etem, ethirim, fenaminosulf, fenapanil, fenitropan, fluotrimazole, furcarbanil, furconazole, furconazole-cis, furmecyclox, furophanate, glyodine, griseofulvin, halacrinate, Hercules 3944, hexylthiofos, ICIA0858, isopamphos, isovaledione, mebenil, mecarbinzid, metazoxolon, methfuroxam, methylmercury dicyandiamide, metsulfovax, milneb, mucochloric anhydride, myclozolin, N-3,5-dichlorophenyl-succinimide, N-3-nitrophenylitaconimide, natamycin, N-ethylmercurio-4-toluenesulfonanilide, nickel bis(dimethyldithiocarbamate), OCH, phenylmercury dimethyldithiocarbamate, phenylmercury nitrate, phosdiphen, prothiocarb; prothiocarb hydrochloride, pyracarbolid, pyridinitril, pyroxychlor, pyroxyfur, quinacetol; quinacetol sulfate, quinazamid, quinconazole, rabenzazole, salicylanilide, SSF-109, sultropen, tecoram, thiadifluor, thicyofen, thiochlorfenphim, thiophanate, thioquinox, tioxymid, triamiphos, triarimol, triazbutil, trichlamide, urbacid, XRD-563, and zarilamid, IK-1140, and any combinations thereof.

Additionally, the compounds of the present invention may be combined with other pesticides, including insecticides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the compounds of the present invention in the medium selected for application, and not antagonistic to the activity of the present compounds to form pesticidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure may be applied in conjunction with one or more other pesticides to control a wider variety of undesirable pests. When used in conjunction with other pesticides, the presently claimed compounds may be formulated with the other pesticide(s), tank mixed with the other pesticide(s) or applied sequentially with the other pesticide(s). Typical insecticides include, but are not limited to: antibiotic insecticides such as allosamidin and thuringiensin; macrocyclic lactone insecticides such as spinosad and spinetoram; avermectin insecticides such as abamectin, doramectin, emamectin, eprinomectin, ivermectin and selamectin; milbemycin insecticides such as lepimectin, milbemectin, milbemycin oxime and moxidectin; arsenical insecticides such as calcium arsenate, copper acetoarsenite, copper arsenate, lead arsenate, potassium arsenite and sodium arsenite; botanical insecticides such as anabasine, azadirachtin, d-limonene, nicotine, pyrethrins, cinerins, cinerin I, cinerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II, quassia, rotenone, ryania and sabadilla; carbamate insecticides such as bendiocarb and carbaryl; benzofuranyl methylcarbamate insecticides such as benfuracarb, carbofuran, carbosulfan, decarbofuran and furathiocarb; dimethylcarbamate insecticides dimitan, dimetilan, hyquincarb and pirimicarb; oxime carbamate insecticides such as alanycarb, aldicarb, aldoxycarb, butocarboxim, butoxycarboxim, methomyl, nitrilacarb, oxamyl, tazimcarb, thiocarboxime, thiodicarb and thiofanox; phenyl methylcarbamate insecticides such as allyxycarb, aminocarb, bufencarb, butacarb, carbanolate, cloethocarb, dicresyl, dioxacarb, EMPC, ethiofencarb, fenethacarb, fenobucarb, isoprocarb, methiocarb, metolcarb, mexacarbate, promacyl, promecarb, propoxur, trimethacarb, XMC and xylylcarb; dessicant insecticides such as boric acid, diatomaceous earth and silica gel; diamide insecticides such as chlorantraniliprole, cyantraniliprole and flubendiamide; dinitrophenol insecticides such as dinex, dinoprop, dinosam and DNOC; fluorine insecticides such as barium hexafluorosilicate, cryolite, sodium fluoride, sodium hexafluorosilicate and sulfluramid; formamidine insecticides such as amitraz, chlordimeform, formetanate and formparanate; fumigant insecticides such as acrylonitrile, carbon disulfide, carbon tetrachloride, chloroform, chloropicrin, para-dichlorobenzene, 1,2-dichloropropane, ethyl formate, ethylene dibromide, ethylene dichloride, ethylene oxide, hydrogen cyanide, iodomethane, methyl bromide, methylchloroform, methylene chloride, naphthalene, phosphine, sulfuryl fluoride and tetrachloroethane; inorganic insecticides such as borax, calcium polysulfide, copper oleate, mercurous chloride, potassium thiocyanate and sodium thiocyanate; chitin synthesis inhibitors such as bistrifluoron, buprofezin, chlorfluazuron, cyromazine, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, penfluoron, teflubenzuron and triflumuron; juvenile hormone mimics such as epofenonane, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen and triprene; juvenile hormones such as juvenile hormone I, juvenile hormone II and juvenile hormone III; moulting hormone agonists such as chromafenozide, halofenozide, methoxyfenozide and tebufenozide; moulting hormones such as α-ecdysone and ecdysterone; moulting inhibitors such as diofenolan; precocenes such as precocene I, precocene II and precocene III; unclassified insect growth regulators such as dicyclanil; nereistoxin analogue insecticides such as bensultap, cartap, thiocyclam and thiosultap; nicotinoid insecticides such as flonicamid; nitroguanidine insecticides such as clothianidin, dinotefuran, imidacloprid and thiamethoxam; nitromethylene insecticides such as nitenpyram and nithiazine; pyridylmethyl-amine insecticides such as acetamiprid, imidacloprid, nitenpyram and thiacloprid; organochlorine insecticides such as bromo-DDT, camphechlor, DDT, pp′-DDT, ethyl-DDD, HCH, gamma-HCH, lindane, methoxychlor, pentachlorophenol and TDE; cyclodiene insecticides such as aldrin, bromocyclen, chlorbicyclen, chlordane, chlordecone, dieldrin, dilor, endosulfan, alpha-endosulfan, endrin, HEOD, heptachlor, HHDN, isobenzan, isodrin, kelevan and mirex; organophosphate insecticides such as bromfenvinfos, chlorfenvinphos, crotoxyphos, dichlorvos, dicrotophos, dimethylvinphos, fospirate, heptenophos, methocrotophos, mevinphos, monocrotophos, naled, naftalofos, phosphamidon, propaphos, TEPP and tetrachlorvinphos; organothiophosphate insecticides such as dioxabenzofos, fosmethilan and phenthoate; aliphatic organothiophosphate insecticides such as acethion, amiton, cadusafos, chlorethoxyfos, chlormephos, demephion, demephion-O, demephion-S, demeton, demeton-O, demeton-S, demeton-methyl, demeton-O-methyl, demeton-5-methyl, demeton-5-methylsulphon, disulfoton, ethion, ethoprophos, IPSP, isothioate, malathion, methacrifos, oxydemeton-methyl, oxydeprofos, oxydisulfoton, phorate, sulfotep, terbufos and thiometon; aliphatic amide organothiophosphate insecticides such as amidithion, cyanthoate, dimethoate, ethoate-methyl, formothion, mecarbam, omethoate, prothoate, sophamide and vamidothion; oxime organothiophosphate insecticides such as chlorphoxim, phoxim and phoxim-methyl; heterocyclic organothiophosphate insecticides such as azamethiphos, coumaphos, coumithoate, dioxathion, endothion, menazon, morphothion, phosalone, pyraclofos, pyridaphenthion and quinothion; benzothiopyran organothiophosphate insecticides such as dithicrofos and thicrofos; benzotriazine organothiophosphate insecticides such as azinphos-ethyl and azinphos-methyl; isoindole organothiophosphate insecticides such as dialifos and phosmet; isoxazole organothiophosphate insecticides such as isoxathion and zolaprofos; pyrazolopyrimidine organothiophosphate insecticides such as chlorprazophos and pyrazophos; pyridine organothiophosphate insecticides such as chlorpyrifos and chlorpyrifos-methyl; pyrimidine organothiophosphate insecticides such as butathiofos, diazinon, etrimfos, lirimfos, pirimiphos-ethyl, pirimiphos-methyl, primidophos, pyrimitate and tebupirimfos; quinoxaline organothiophosphate insecticides such as quinalphos and quinalphos-methyl; thiadiazole organothiophosphate insecticides such as athidathion, lythidathion, methidathion and prothidathion; triazole organothiophosphate insecticides such as isazofos and triazophos; phenyl organothiophosphate insecticides such as azothoate, bromophos, bromophos-ethyl, carbophenothion, chlorthiophos, cyanophos, cythioate, dicapthon, dichlofenthion, etaphos, famphur, fenchlorphos, fenitrothion fensulfothion, fenthion, fenthion-ethyl, heterophos, jodfenphos, mesulfenfos, parathion, parathion-methyl, phenkapton, phosnichlor, profenofos, prothiofos, sulprofos, temephos, trichlormetaphos-3 and trifenofos; phosphonate insecticides such as butonate and trichlorfon; phosphonothioate insecticides such as mecarphon; phenyl ethylphosphonothioate insecticides such as fonofos and trichloronat; phenyl phenylphosphonothioate insecticides such as cyanofenphos, EPN and leptophos; phosphoramidate insecticides such as crufomate, fenamiphos, fosthietan, mephosfolan, phosfolan and pirimetaphos; phosphoramidothioate insecticides such as acephate, isocarbophos, isofenphos, isofenphos-methyl, methamidophos and propetamphos; phosphorodiamide insecticides such as dimefox, mazidox, mipafox and schradan; oxadiazine insecticides such as indoxacarb; oxadiazoline insecticides such as metoxadiazone; phthalimide insecticides such as dialifos, phosmet and tetramethrin; pyrazole insecticides such as tebufenpyrad, tolefenpyrad; phenylpyrazole insecticides such as acetoprole, ethiprole, fipronil, pyrafluprole, pyriprole and vaniliprole; pyrethroid ester insecticides such as acrinathrin, allethrin, bioallethrin, barthrin, bifenthrin, bioethanomethrin, cyclethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, gamma-cyhalothrin, lambda-cyhalothrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, cyphenothrin, deltamethrin, dimefluthrin, dimethrin, empenthrin, fenfluthrin, fenpirithrin, fenpropathrin, fenvalerate, esfenvalerate, flucythrinate, fluvalinate, tau-fluvalinate, furethrin, imiprothrin, metofluthrin, permethrin, biopermethrin, transpermethrin, phenothrin, prallethrin, profluthrin, pyresmethrin, resmethrin, bioresmethrin, cismethrin, tefluthrin, terallethrin, tetramethrin, tralomethrin and transfluthrin; pyrethroid ether insecticides such as etofenprox, flufenprox, halfenprox, protrifenbute and silafluofen; pyrimidinamine insecticides such as flufenerim and pyrimidifen; pyrrole insecticides such as chlorfenapyr; tetramic acid insecticides such as spirotetramat; tetronic acid insecticides such as spiromesifen; thiourea insecticides such as diafenthiuron; urea insecticides such as flucofuron and sulcofuron; and unclassified insecticides such as closantel, copper naphthenate, crotamiton, EXD, fenazaflor, fenoxacrim, hydramethylnon, isoprothiolane, malonoben, metaflumizone, nifluridide, plifenate, pyridaben, pyridalyl, pyrifluquinazon, rafoxanide, sulfoxaflor, triarathene and triazamate, and any combinations thereof.

Additionally, the compounds of the present invention may be combined with herbicides that are compatible with the compounds of the present invention in the medium selected for application, and not antagonistic to the activity of the present compounds to form pesticidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure may be applied in conjunction with one or more herbicides to control a wide variety of undesirable plants. When used in conjunction with herbicides, the presently claimed compounds may be formulated with the herbicide(s), tank mixed with the herbicide(s) or applied sequentially with the herbicide(s). Typical herbicides include, but are not limited to: amide herbicides such as allidochlor, beflubutamid, benzadox, benzipram, bromobutide, cafenstrole, CDEA, cyprazole, dimethenamid, dimethenamid-P, diphenamid, epronaz, etnipromid, fentrazamide, flupoxam, fomesafen, halosafen, isocarbamid, isoxaben, napropamide, naptalam, pethoxamid, propyzamide, quinonamid and tebutam; anilide herbicides such as chloranocryl, cisanilide, clomeprop, cypromid, diflufenican, etobenzanid, fenasulam, flufenacet, flufenican, mefenacet, mefluidide, metamifop, monalide, naproanilide, pentanochlor, picolinafen and propanil; arylalanine herbicides such as benzoylprop, flampropand flamprop-M; chloroacetanilide herbicides such as acetochlor, alachlor, butachlor, butenachlor, delachlor, diethatyl, dimethachlor, metazachlor, metolachlor, S-metolachlor, pretilachlor, propachlor, propisochlor, prynachlor, terbuchlor, thenylchlor and xylachlor; sulfonanilide herbicides such as benzofluor, perfluidone, pyrimisulfan and profluazol; sulfonamide herbicides such as asulam, carbasulam, fenasulam and oryzalin; thioamide herbicides such as chlorthiamid; antibiotic herbicides such as bilanafos; benzoic acid herbicides such as chloramben, dicamba, 2,3,6-TBA and tricamba; pyrimidinyloxybenzoic acid herbicides such as bispyribac and pyriminobac; pyrimidinylthiobenzoic acid herbicides such as pyrithiobac; phthalic acid herbicides such as chlorthal; picolinic acid herbicides such as aminopyralid, clopyralid and picloram; quinolinecarboxylic acid herbicides such as quinclorac and quinmerac; arsenical herbicides such as cacodylic acid, CMA, DSMA, hexaflurate, MAA, MAMA, MSMA, potassium arsenite and sodium arsenite; benzoylcyclohexanedione herbicides such as mesotrione, sulcotrione, tefuryltrione and tembotrione; benzofuranyl alkylsulfonate herbicides such as benfuresate and ethofumesate; benzothiazole herbicides such as benzazolin; carbamate herbicides such as asulam, carboxazole chlorprocarb, dichlormate, fenasulam, karbutilate and terbucarb; carbanilate herbicides such as barban, BCPC, carbasulam, carbetamide, CEPC, chlorbufam, chlorpropham, CPPC, desmedipham, phenisopham, phenmedipham, phenmedipham-ethyl, propham and swep; cyclohexene oxime herbicides such as alloxydim, butroxydim, clethodim, cloproxydim, cycloxydim, profoxydim, sethoxydim, tepraloxydim and tralkoxydim; cyclopropylisoxazole herbicides such as isoxachlortole and isoxaflutole; dicarboximide herbicides such as cinidon-ethyl, flumezin, flumiclorac, flumioxazin and flumipropyn; dinitroaniline herbicides such as benfluralin, butralin, dinitramine, ethalfluralin, fluchloralin, isopropalin, methalpropalin, nitralin, oryzalin, pendimethalin, prodiamine, profluralin and trifluralin; dinitrophenol herbicides such as dinofenate, dinoprop, dinosam, dinoseb, dinoterb, DNOC, etinofen and medinoterb; diphenyl ether herbicides such as ethoxyfen; nitrophenyl ether herbicides such as acifluorfen, aclonifen, bifenox, chlomethoxyfen, chlomitrofen, etnipromid, fluorodifen, fluoroglycofen, fluoronitrofen, fomesafen, furyloxyfen, halosafen, lactofen, nitrofen, nitrofluorfen and oxyfluorfen; dithiocarbamate herbicides such as dazomet and metam; halogenated aliphatic herbicides such as alorac, chloropon, dalapon, flupropanate, hexachloroacetone, iodomethane, methyl bromide, monochloroacetic acid, SMA and TCA; imidazolinone herbicides such as imazamethabenz, imazamox, imazapic, imazapyr, imazaquin and imazethapyr; inorganic herbicides such as ammonium sulfamate, borax, calcium chlorate, copper sulfate, ferrous sulfate, potassium azide, potassium cyanate, sodium azide, sodium chlorate and sulfuric acid; nitrile herbicides such as bromobonil, bromoxynil, chloroxynil, dichlobenil, iodobonil, ioxynil and pyraclonil; organophosphorus herbicides such as amiprofos-methyl, anilofos, bensulide, bilanafos, butamifos, 2,4-DEP, DMPA, EBEP, fosamine, glufosinate, glufosinate-P, glyphosate and piperophos; phenoxy herbicides such as bromofenoxim, clomeprop, 2,4-DEB, 2,4-DEP, difenopenten, disul, erbon, etnipromid, fenteracol and trifopsime; oxadiazoline herbicides such as methazole, oxadiargyl, oxadiazon; oxazole herbicides such as fenoxasulfone; phenoxyacetic herbicides such as 4-CPA, 2,4-D, 3,4-DA, MCPA, MCPA-thioethyl and 2,4,5-T; phenoxybutyric herbicides such as 4-CPB, 2,4-DB, 3,4-DB, MCPB and 2,4,5-TB; phenoxypropionic herbicides such as cloprop, 4-CPP, dichlorprop, dichlorprop-P, 3,4-DP, fenoprop, mecopropand mecoprop-P; aryloxyphenoxypropionic herbicides such as chlorazifop, clodinafop, clofop, cyhalofop, diclofop, fenoxaprop, fenoxaprop-P, fenthiaprop, fluazifop, fluazifop-P, haloxyfop, haloxyfop-P, isoxapyrifop, metamifop, propaquizafop, quizalofop, quizalofop-P and trifop; phenylenediamine herbicides such as dinitramine and prodiamine; pyrazole herbicides such as pyroxasulfone; benzoylpyrazole herbicides such as benzofenap, pyrasulfotole, pyrazolynate, pyrazoxyfen, and topramezone; phenylpyrazole herbicides such as fluazolate, nipyraclofen, pioxaden and pyraflufen; pyridazine herbicides such as credazine, pyridafol and pyridate; pyridazinone herbicides such as brompyrazon, chloridazon, dimidazon, flufenpyr, metflurazon, norflurazon, oxapyrazon and pydanon; pyridine herbicides such as aminopyralid, cliodinate, clopyralid, dithiopyr, fluoroxypyr, haloxydine, picloram, picolinafen, pyriclor, thiazopyr and triclopyr; pyrimidinediamine herbicides such as iprymidam and tioclorim; quaternary ammonium herbicides such as cyperquat, diethamquat, difenzoquat, diquat, morfamquat and paraquat; thiocarbamate herbicides such as butylate, cycloate, di-allate, EPTC, esprocarb, ethiolate, isopolinate, methiobencarb, molinate, orbencarb, pebulate, prosulfocarb, pyributicarb, sulfallate, thiobencarb, tiocarbazil, tri-allate and vernolate; thiocarbonate herbicides such as dimexano, EXD and proxan; thiourea herbicides such as methiuron; triazine herbicides such as dipropetryn, indaziflam, triaziflam and trihydroxytriazine; chlorotriazine herbicides such as atrazine, chlorazine, cyanazine, cyprazine, eglinazine, ipazine, mesoprazine, procyazine, proglinazine, propazine, sebuthylazine, simazine, terbuthylazine and trietazine; methoxytriazine herbicides such as atraton, methometon, prometon, secbumeton, simeton and terbumeton; methylthiotriazine herbicides such as ametryn, aziprotryne, cyanatryn, desmetryn, dimethametryn, methoprotryne, prometryn, simetryn and terbutryn; triazinone herbicides such as ametridione, amibuzin, hexazinone, isomethiozin, metamitron and metribuzin; triazole herbicides such as amitrole, cafenstrole, epronaz and flupoxam; triazolone herbicides such as amicarbazone, bencarbazone, carfentrazone, flucarbazone, ipfencarbazone, propoxycarbazone, sulfentrazone and thiencarbazone-methyl; triazolopyrimidine herbicides such as cloransulam, diclosulam, florasulam, flumetsulam, metosulam, penoxsulam and pyroxsulam; uracil herbicides such as benzfendizone, bromacil, butafenacil, flupropacil, isocil, lenacil, saflufenacil and terbacil; urea herbicides such as benzthiazuron, cumyluron, cycluron, dichloralurea, diflufenzopyr, isonoruron, isouron, methabenzthiazuron, monisouron and noruron; phenylurea herbicides such as anisuron, buturon, chlorbromuron, chloreturon, chlorotoluron, chloroxuron, daimuron, difenoxuron, dimefuron, diuron, fenuron, fluometuron, fluothiuron, isoproturon, linuron, methiuron, methyldymron, metobenzuron, metobromuron, metoxuron, monolinuron, monuron, neburon, parafluoron, phenobenzuron, siduron, tetrafluoron and thidiazuron; pyrimidinylsulfonylurea herbicides such as amidosulfuron, azimsulfuron, bensulfuron, chlorimuron, cyclosulfamuron, ethoxysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron, foramsulfuron, halosulfuron, imazosulfuron, mesosulfuron, metazosulfuron, nicosulfuron, orthosulfamuron, oxasulfuron, primisulfuron, propyrisulfuron, pyrazosulfuron, rimsulfuron, sulfometuron, sulfosulfuron and trifloxysulfuron; triazinylsulfonylurea herbicides such as chlorsulfuron, cinosulfuron, ethametsulfuron, iodosulfuron, metsulfuron, prosulfuron, thifensulfuron, triasulfuron, tribenuron, triflusulfuron and tritosulfuron; thiadiazolylurea herbicides such as buthiuron, ethidimuron, tebuthiuron, thiazafluoron and thidiazuron; and unclassified herbicides such as acrolein, allyl alcohol, aminocyclopyrachlor, azafenidin, bentazone, benzobicyclon, bicyclopyrone, buthidazole, calcium cyanamide, cambendichlor, chlorfenac, chlorfenprop, chlorflurazole, chlorflurenol, cinmethylin, clomazone, CPMF, cresol, cyanamide, ortho-dichlorobenzene, dimepiperate, endothal, fluoromidine, fluridone, fluorochloridone, flurtamone, fluthiacet, indanofan, methyl isothiocyanate, OCH, oxaziclomefone, pentachlorophenol, pentoxazone, phenylmercury acetate, prosulfalin, pyribenzoxim, pyriftalid, quinoclamine, rhodethanil, sulglycapin, thidiazimin, tridiphane, trimeturon, tripropindan and tritac.

Another embodiment of the present disclosure is a method for the control or prevention of fungal attack. This method comprises applying to the soil, plant, roots, foliage, seed or locus of the fungus, or to a locus in which the infestation is to be prevented (for example applying to cereal or grape plants), a fungicidal effective amount of one or more of the compounds of Formula I. The compounds are suitable for treatment of various plants at fungicidal levels, while exhibiting low phytotoxicity. The compounds may be useful both in a protectant and/or an eradicant fashion.

The compounds have been found to have significant fungicidal effect particularly for agricultural use. Many of the compounds are particularly effective for use with agricultural crops and horticultural plants.

It will be understood by those in the art that the efficacy of the compound for the foregoing fungi establishes the general utility of the compounds as fungicides.

The compounds have broad ranges of activity against fungal pathogens. Exemplary pathogens may include, but are not limited to, wheat leaf blotch (Septoria tritici, also known as Mycosphaerella graminicola), apple scab (Venturia inaequalis), and Cercospora leaf spots of sugar beets (Cercospora beticola), peanuts (Cercospora arachidicola and Cercosporidium personatum) and other crops, and black sigatoka of bananas (Mycosphaerella fujiensis). The exact amount of the active material to be applied is dependent not only on the specific active material being applied, but also on the particular action desired, the fungal species to be controlled, and the stage of growth thereof, as well as the part of the plant or other product to be contacted with the compound. Thus, all the compounds, and formulations containing the same, may not be equally effective at similar concentrations or against the same fungal species.

The compounds are effective in use with plants in a disease-inhibiting and phytologically acceptable amount. The term “disease inhibiting and phytologically acceptable amount” refers to an amount of a compound that kills or inhibits the plant disease for which control is desired, but is not significantly toxic to the plant. This amount will generally be from about 0.1 to about 1000 ppm (parts per million), with 1 to 500 ppm being preferred. The exact concentration of compound required varies with the fungal disease to be controlled, the type of formulation employed, the method of application, the particular plant species, climate conditions, and the like. A suitable application rate is typically in the range from about 0.10 to about 4 pounds/acre (about 0.01 to 0.45 grams per square meter, g/m²).

Any range or desired value given herein may be extended or altered without losing the effects sought, as is apparent to the skilled person for an understanding of the teachings herein.

The compounds of Formula I may be made using well-known chemical procedures. Intermediates not specifically mentioned in this disclosure are either commercially available, may be made by routes disclosed in the chemical literature, or may be readily synthesized from commercial starting materials utilizing standard procedures.

The following examples are presented to illustrate the various aspects of the compounds of the present disclosure and should not be construed as limitations to the claims.

EXAMPLES Preparation of 5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-amine (1)

To a solution of 4-fluorobenzyl alcohol (2.56 g, 20.3 mmol) in 1,4-dioxane (20 mL) was added 60% NaH (0.813 g, 20.3 mmol) in several portions over a period of 10 min. To the magnetically stirred solution was added 4-amino-2-chloro-5-fluoropyrimidine* (2.00 g, 13.6 mmol) and the mixture was stirred at room temperature until gas evolution subsided. The reaction mixture was then heated in a CEM Discover microwave reactor at 120° C. for 90 min. The cooled reaction mixture was partitioned between ethyl acetate and water, the organic phase was concentrated, and the product was purified by column chromatography (hexane/ethyl acetate gradient) to yield 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-amine (1.66 g, 52% yield) as a white solid: mp 129-131° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.91 (d, J=2.6 Hz, 1H), 7.42 (m, 2H), 7.03 (m, 2H), 5.27 (s, 2H), 5.05 (br s, 2H); MS (ESI) m/z 238 (M+H)⁺. *4-Amino-2-chloro-5-fluoropyrimidine can be purchased commercially or can be prepared through known literature methods. 1. Hayashi, T.; Kawakami, T. JP Patent 2005126389 2. Durr, G. J. J. Med. Chem. 1965, 8(2), 253.

2-(3-Bromobenzyloxy)-5-fluoropyrimidin-4-ylamine (2)

To a magnetically stirred mixture of t-BUOK (1.0 M in t-BuOH, 1.36 ml, 1.36 mmol) was added (3-bromophenyl)methanol (0.25 g, 1.36 mmol). To the resulting solution was added 4-amino-2-chloro-5-fluoropyrimidine (0.10 g, 0.68 mmol) and the mixture was capped and stirred at 90° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with water, and the resulting precipitate was collected by filtration. The solid was washed with water, washed with cyclohexane, and dried in a vacuum oven. A CH₂Cl₂ solution of the compound was loaded onto Biotage SCX column and eluted with CH₂Cl₂ followed by 2.0 M NH₃ in MeOH. The solvent was evaporated under reduced pressure to give the title compound (0.100 g, 49%) as an off-white solid: mp 143-145° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (d, J=2.5 Hz, 1H), 7.61 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 5.28 (s, 2H), 5.20 (br s, 2H); GCMS (EI) m/z 297, 299 (M)⁺.

Preparation of 5-Fluoro-2-[1-(4-fluorophenyl)ethoxy]pyrimidin-4-ylamine (3)

To a magnetically stirred mixture of 4-amino-2-chloro-5-fluoropyrimidine (11.10 g, 75.2 mmol) in 1-(4-fluorophenyl)ethanol (11.70 g, 82.8 mmol) was added a 1.0 M solution of t-BuOK in t-BuOH (82.8 mL, 82.8 mmol) in one portion, and the resulting tan mixture was heated to reflux and stirred for 24 h. The solvent was removed in vacuo and the resulting red-orange oil was purified by flash chromatography (SiO₂, 0→10% MeOH/CH₂Cl₂) to give 5.5 g of red-orange oil. The oil was suspended in hexanes (100 mL) and stirred for 16 h. Water (100 mL) was added to the unchanged mixture, and the biphasic system was stirred vigorously for 1 h. The resulting cream colored solid was collected by vacuum filtration, washed with warm water (55° C., 2×100 mL), and dried under vacuum at 55° C. for 16 h to give 5-fluoro-2-[1-(4-fluorophenyl)ethoxy]pyrimidin-4-ylamine (3.30 g, 17.2% yield) as a white solid: mp 96-98° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J=2.6 Hz, 1H), 7.42-7.38 (m, 2H), 7.03-6.97 (m, 2H), 5.99 (q, J=6.6 Hz, 1H), 5.09 (br s, 2H), 1.61 (d, J=6.6 Hz, 3H); MS (ESI) m/z 252 (M+H)⁺,

m/z 250 (M−H)⁻.

Preparation of 1-Phenyl-ethanone-O-(4-amino-5-fluoropyrimidin-2-yl)oxime (4)

To a magnetically stirred mixture of 4-amino-2-chloro-5-fluoropyrimidine (0.10 g, 0.68 mmol) and acetophenone oxime (0.092 g, 0.68 mmol) in dry DMF (3 mL) in a 5 mL Biotage Iniator microwave vessel was added NaH (0.027 g of a 60 wt. % suspension, 0.68 mmol) under a N₂ atmosphere. After gas evolution ceased, the resulting mixture was sealed with a Biotage Initiator microwave septa cap and heated to 100° C. in a Biotage Initiator microwave for 60 min. The contents were poured into a vial with water (5 mL) and CH₂Cl₂ (5 mL), and neutralized with a few drops of 2N HCl. The phases were separated and the organic extract was dried over MgSO₄, filtered, and evaporated under a stream of nitrogen. The crude contents were purified on silica (EtOAc/hexanes gradient) and evaporation of the product fractions gave 0.057 g (34%) of 1-phenyl-ethanone-O-(4-amino-5-fluoro-pyrimidin-2-yl)oxime as an off-white solid: mp 163-165° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.04 (d, J=2.6 Hz, 1H), 7.75 (m, 2H), 7.42 (m, 3H), 5.25 (bs, 2H), 2.51 (s, 3H); HPLC-MS (ESI) m/z 247 (M+H)⁺.

Preparation of 5-Fluoro-2-(thiophen-2-ylmethoxy)-pyrimidin-4-ylamine (5)

To a mixture of 4-amino-2-chloro-5-fluoropyrimidine (2.00 g, 13.5 mmol) and thiophen-2-ylmethanol (1.92 g, 16.9 mmol) with a magnetic stir bar in a 20 mL Biotage Initiator microwave reaction vessel was added t-BuOK (17.0 mL of 1M in t-BuOH, 17.0 mmol). The resulting mixture was sealed with a Biotage Initiator microwave septa cap and heated in a Biotage Initiator microwave to 100° C. for 30 min. The heating cycle was repeated (2×) for a total reaction time of 90 min. The contents were poured into ice-water and the pH was adjusted to neutral with 2N HCl. The resulting solid was filtered and washed with water (2×) and then 20% ether/hexanes (100 mL). The remaining solid was dried overnight at 50° C. under vacuum to give 4.17 g (68%) of 5-fluoro-2-(thiophen-2-ylmethoxy)pyrimidin-4-ylamine as a pale yellow powder: mp 92-94° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J=2.7 Hz, 1H), 7.29 (m, 1H), 7.13 (d, J=3.6 Hz, 1H), 6.97 (m, 1H), 5.46 (s, 2H), 5.17 (br s, 2H); MS (ESI) m/z 226 (M+H)⁺.

Preparation of N-[5-Fluoro-2-(thiophen-2-ylmethoxy)pyrimidin-4-yl]acetamide (6)

In a 2 dram screw cap vial, a solution of 5-fluoro-2-(thiophen-2-ylmethoxy)-pyrimidin-4-ylamine (0.10 g, 0.4 mmol) in CH₂Cl₂ was treated with acetyl chloride (0.032 g, 0.4 mmol,) and PS-NMM (0.42 g, 0.8 mmol), a resin-bound equivalent of N-methyl morpholine (NMM). The mixture was shaken at RT for 12 h. The reaction mixture was filtered and the solvent evaporated to yield 0.084 g (75%) of the title compound as white solid: mp 134-136° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.24 (d, J=2.6 Hz, 1H), 7.86 (bs, 1H), 7.31 (m, 1H), 7.23 (m, 1H), 7.00 (m, 1H), 5.54 (s, 2H), 2.58 (s, 3H); MS (ESI) m/z 268 (M+H)⁺.

Preparation of [5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-(4-methylpiperazin-1-ylmethyl)amine (7)

To a magnetically stirred mixture of paraformaldehyde (0.24 g, 8 mmol) in CH₂Cl₂ (20 mL) was added N-methylpiperazine (0.80 g, 8.0 mmol). The suspension was stirred overnight at ambient temperature on an orbital shaker, and then 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.47 g, 2.0 mmol) was added. The resulting mixture was stirred over the weekend at RT. The solvent was evaporated and the crude residue was washed twice with 50% ether/petroleum ether and dried under a stream of N₂ to give 0.21 g (30%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl](4-methylpiperazin-1-ylmethyl)amine as a beige solid: mp 125-126° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J=2.3 Hz, 1H), 7.43 (m, 2H), 7.03 (t, J=8.5 Hz, 2H), 5.40 (bs, 1H), 5.27 (s, 2H), 4.41 (d, J=6.8 Hz, 2H), 2.63 (bs, 4H), 2.47 (bs, 4H), 2.30 (s, 3H); HPLC-MS (ESI) m/z 350 (M+H)⁺.

Preparation of [5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]triethylsilanylamine

To a magnetically stirred mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.25 g, 1.05 mmol) in dry THF (5 mL) at 0° C. was added NaH (0.042 g of 60 wt. % suspension in mineral oil, 1.05 mmol). When bubbling ceased, triethylsilyl chloride (0.158 g, 1.05 mmol) was added dropwise (neat) via syringe. After stirring overnight at ambient temperature, the reaction mixture was poured into ether and washed with a mixture of aqueous saturated sodium bicarbonate and brine solution. The organic layer was separated, dried over Na₂SO₄, filtered, and evaporated to give a white solid. This crude material was purified on silica by column chromatography (EtOAc/hexanes gradient) to give 0.121 g (33%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-triethylsilanylamine as a clear yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J=2.5 Hz, 1H), 7.39 (m, 2H), 7.03 (t, J=8.6 Hz, 2H), 5.27 (s, 2H), 4.53 (s, 1H), 0.99 (m, 9H), 0.83 (m, 6H); HPLC-MS (ESI) m/z 352 (M+H)⁺.

Preparation of [5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]bis-carbamic acid 4-fluorophenyl ester (9)

To a magnetically stirred ice-cold mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.25 g, 1.05 mmol) in dry THF (5 mL) was added NaH (0.042 g of a 60 wt. % suspension in mineral oil, 1.05 mmol). After bubbling ceased, 4-fluorophenyl chloroformate (0.184 g, 1.05 mmol) was added dropwise as a solution in dry THF. After stirring one hour, the reaction was partitioned between EtOAc and brine solution. The organic extract was dried over Na₂SO₄, filtered, and evaporated. The crude material was purified on silica using a gradient of EtOAc/Hex and then MeOH/EtOAc to give 0.054 g (14%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]bis-carbamic acid 4-fluoro-phenyl ester as a white solid: mp 103-105° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.58 (d, J=2.2 Hz, 1H), 7.43 (m, 2H), 7.08 (m, 10H), 5.40 (s, 2H); HPLC-MS (ESI) m/z 514 (M+H)⁺.

Preparation of [5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]carbamic acid phenyl ester (10)

To a stirred mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.20 g, 0.84 mmol) in dry THF (3 mL) at ice-bath temperature was added NaH (0.034 g of 60 wt. % suspension in mineral oil, 0.84 mmol). When bubbling ceased, the resulting mixture was transferred (dropwise) via cannula to an ice-cold, stirred mixture of diphenyl carbonate (1.8 g, 8.4 mmol) in dry THF (5 mL). The mixture was stirred overnight, poured into EtOAc, and washed with saturated aq. NH₄Cl solution followed by brine solution. The EtOAc layer was separated, dried over Na₂SO₄, filtered, and evaporated. The crude material was purified on silica gel using a gradient of EtOAc and hexanes to give 0.063 g (21%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]carbamic acid phenyl ester as a white solid: mp 129-131° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.28 (d, J=2.3 Hz, 1H), 7.43 (m, 5H), 7.30-7.20 (m, 2H), 7.02 (t, J=8.6 Hz, 2H), 5.38 (s, 2H); HPLC-MS (ESI) m/z 358 (M+H)⁺.

Preparation of N-[5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]oxalamic acid ethyl ester (11)

To a mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.235 g, 0.99 mmol), N-methyl morpholine on polystyrene (0.538 g, 1.24 mmol), and CH₂Cl₂ (5 mL) was added chloro-oxo-acetic acid ethyl ester (0.135 g, 0.99 mmol) and the resulting mixture was agitated on an orbital shaker for 16 h. The reaction contents were filtered onto an acidic SPE cartridge and eluted with CH₂Cl₂. The CH₂Cl₂ filtrate was evaporated to give 0.165 g (50%) of N-[5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]oxalamic acid ethyl ester as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ 9.21 (bs, 1H), 8.38 (d, J=2.3 Hz, 1H), 7.48 (m, 2H), 7.03 (t, J=8.5 Hz, 2H), 5.40 (s, 2H), 4.48 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H); HPLC-MS (ESI) m/z 338 (M+H)⁺.

Preparation of 3,4-Dichloroisothiazole-5-carboxylic acid [5-fluoro-2-(4-fluorobenzyl-oxy)pyrimidin-4-yl]amide (12)

To a suspension of 3,4-dichloroisothiazole-5-carboxylic acid (0.15 g, 0.76 mmol) in oxalyl chloride (2 mL) was added a catalytic amount of dimethylformamide (2 drops) and the mixture was heated to 80° C. and stirred for 2 h. The excess oxalyl chloride was removed on the rotary evaporator. Meanwhile, 5-fluoro-2-(4-fluorobenzyloxy)-pyrimidin-4-ylamine (0.17 g, 0.68 mmol) was dissolved in THF (1 mL), treated with LiHMDS (1M in THF, 0.76 mL, 0.76 mmol) and stirred for 10 min. The freshly prepared 3,4-dichlorothiazole-5-carbonyl chloride*, dissolved in THF (1 mL), was added and the reaction was capped and stirred for 12 h. The reaction was diluted with water and the target compound was extracted with CH₂Cl₂ (3×5 mL). The combined extracts were dried over MgSO₄ and then evaporated under reduced pressure. The mixture was eluted with CH₂Cl₂ through an anionic-exchange solid phase extraction column and then further purified by reverse-phase chromatography to give 3,4-dichloroisothiazole-5-carboxylic acid [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]amide (0.035 g, 12%) as a tan solid: mp 87-90° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 11.78 (s, 1H), 8.67 (s, 1H), 7.51-7.48 (m, 2H), 7.24-7.19 (m, 2H), 5.25 (s, 2H); MS (ESI) m/z 417 (M+H)⁺, 415 (M−H)⁻. *Nagata, T.; Kogure, A.; Yonekura, N.; Hanai, R.; Kaneko, I.; Nakano, Y. JP 2007211002 A

Preparation of [5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]phosphoramidic acid diethyl ester (13)

To a magnetically stirred solution of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.10 g, 0.42 mmol) in dry THF (5 mL) under a nitrogen atmosphere was added NaH (0.017 g of a 60 wt. % suspension, 0.42 mmol) and the mixture was stirred until bubbling ceased. Diethyl chlorophosphate (0.073 g, 0.42 mmol) was added dropwise, and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was evaporated to dryness and the residue dissolved in EtOAc and washed with saturated aqueous NH₄Cl solution. The organic layer was separated, dried over Na₂SO₄, filtered, and evaporated. The crude material was purified on silica (acetone/CH₂Cl₂ gradient) to give 0.017 g (11%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]phosphoramidic acid diethyl ester as a white solid: mp 109-111° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.10 (t, J=1.8 Hz, 1H), 7.43 (m, 2H), 7.03 (t, J=8.5 Hz, 2H), 6.18 (br s, 1H), 5.35 (s, 2H), 4.25 (m, 4H), 1.38 (t, J=7.1 Hz, 6H); HPLC-MS (ESI) m/z 374 (M+H)⁺.

Preparation of [5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl](1-methoxypropyl)amine (14)

To a solution of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.10 g, 0.42 mmol) in propionaldehyde (2 mL) was added a catalytic amount of camphorsulfonic acid. The mixture was agitated on an orbital shaker at room temperature for 4 h and then evaporated to dryness. Methanol (2 mL) was added, and the resulting solution was warmed to 60° C. for 1 h. After evaporation, the crude product was purified by reverse phase chromatography to yield the title compound (0.030 g, 24% yield) as a clear, colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.91 (d, J=2.5 Hz, 1H), 7.47-7.41 (m, 2H), 7.09-7.01 (m, 2H), 5.41 (dt, J=9.9 and 6.0 Hz, 1H), 5.30 (s, 2H), 5.2 (bd, J˜10 Hz, 1H), 3.12 (s, 3H), 1.88-1.60 (m, 2H), 0.98 (t, J=7.1 Hz, 3H). HPLC-MS 308 (ES⁻), 310 (ES⁺).

Preparation of [5-Fluoro-2-(4-methylbenzyloxy)pyrimidin-4-ylamino]methanol (16)

To a solution of 5-fluoro-2-(4-methylbenzyloxy)pyrimidin-4-ylamine (0.10 g, 0.43 mmol) in dioxane (2 mL) was added paraformaldehyde (0.060 g, 2 mmol) and the mixture was agitated on an orbital shaker at 90° C. for 16 h, cooled, and evaporated to dryness. Purification by reverse phase chromatography afforded 0.070 g (63%) of the title compound as a white solid: mp 97-98° C.; ¹H NMR (CDCl₃) δ 7.94 (d, J=2.5 Hz, 1H), 7.36 (d, J=7.9 Hz, 2H), 7.19 (d, J=7.9 Hz, 2H), 5.97 (bs, 1H), 5.33 (s, 2H), 5.04-4.99 (m, 2H), 3.39 (t, J=8.0 Hz, 1H), 2.37 (s, 3H); MS (ESI) m/z 264 (M+H)⁺.

Preparation of Benzyloxymethyl[5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]amine

To a mixture of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamino]methanol (0.10 g, 3.7 mmol) in benzyl alcohol (1 mL) was added a catalytic amount of p-toluene sulfonic acid. After 30 min, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The phases were separated and the organic portion was dried over anhydrous Na₂SO₄, filtered and evaporated to obtain the crude product. Purification by reverse phase chromatography afforded 0.094 g (70%) of the title compound as a white solid: mp 64-66° C.; ¹H NMR (CDCl₃) δ 7.93 (d, J=2.7 Hz, 1H), 7.47-7.40 (m, 2H), 7.37-7.29 (m, 5H), 7.08-7.00 (m, 2H), 5.81-5.70 (bm, 1H), 5.29 (s, 2H), 5.12 (d, J=6.9 Hz, 2H), 4.63 (s, 2H); MS (ESI) m/z 358 (M+H)⁺.

Preparation of 2,2-Dimethylpropionic acid[5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamino]methyl ester (19)

To a mixture of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamino]methanol (0.10 g, 0.37 mmol) in pyridine (2 mL) was added trimethylacetyl chloride (0.048 g, 0.40 mmol), and the mixture was agitated on an orbital shaker at 60° C. for 4 h. The reaction mixture was cooled, evaporated to dryness, and partitioned between EtOAc and water. The organic layer was dried over Na₂SO₄, filtered, and evaporated to yield the title compound (0.078 g, 60% yield) as a white solid: mp 134-135° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.97 (d, J=2.5 Hz, 1H), 7.49-7.44 (m, 2H), 7.11-7.03 (m, 2H), 6.17 (bt, J≈7 Hz, 1H), 6.17 (d, J=7.4 Hz, 2H), 5.33 (s, 2H), 1.20 (s, 9H); HPLC-MS m/z 352 (M+H)⁺.

Preparation of N-[5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-N,N dimethyl-formamidine (20)

To a magnetically stirred solution of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (1.00 g, 4.2 mmol) in N,N-dimethylformamide (DMF, 20 mL) was added N,N-dimethylformamide dimethyl acetal (0.55 g, 4.6 mmol) and stirring was continued 16 h at RT. The solution was poured into 100 mL of ice water, whereupon a white precipitate was produced. The mixture was cooled at 0° C. for 1 h and then filtered to produce the title compound (1.10 g, 89%) as a white solid: mp 113-115° C.; ¹H NMR (CDCl₃) δ 8.65 (s, 1H), 8.04 (d, J=2.6 Hz, 1H), 7.46-7.40 (m, 2H), 7.07-6.98 (m, 2H), 5.30 (s, 2H), 3.17 (s, 3H), 3.16 (s, 3H); MS (ESI) m/z 292 (M+H)⁺. Anal. Calcd for C₁₄H₁₄F₂N₄O: C, 57.53; H, 4.83; N, 19.17. Found: C, 57.67; H, 4.84; N, 19.09.

Preparation of [5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-[1-pyrrolidin-1-yl-methylidene]amine (21)

To a solution of N′-[5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-N,N-dimethylformamidine (0.10 g, 0.36 mmol) in toluene (2 mL) was added pyrrolidine (0.051 g, 0.72 mmol) and a catalytic amount of camphorsulfonic acid. The vented vial was placed on an orbital shaker, agitated at 90° C. for 16 h, cooled, and evaporated to dryness. Purification by reverse phase chromatography afforded the title compound (0.060 g, 53% yield) as a white solid: mp 102-103° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.87 (s, 1H), 8.06 (d, J=2.7 Hz, 1H), 7.49-7.42 (m, 2H), 7.09-7.01 (m, 2H), 5.32 (s, 2H), 3.73-3.62 (m, 4H), 2.07-1.96 (m, 4H); HPLC-MS (ESI) m/z 319 (M+H)⁺.

Preparation of N-[5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-N′-hydroxy-formamidine (22)

To a solution of N′-[5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-N′-dimethyl-formamidine (0.10 g, 0.34 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (0.047 g, 0.68 mmol) and the mixture was agitated on an orbital shaker for 1.5 h at 50° C. The reaction mixture was cooled and evaporated to dryness. Water was added to produce a slurry which was filtered to isolate the title compound (0.090 g, 94% yield) as a white solid: mp 169-171° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.15 (d, J=2.2 Hz, 1H), 8.02 (bs, 2H), 7.49-7.43 (m, 2H), 7.11-7.02 (m, 3H), 5.35 (s, 2H); HPLC-MS (ESI) m/z 281 (M+H)⁺, 279 (M−H)⁻.

Preparation of N-[5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-N′-cyanoformamidine (23)

Cyanamide (8.00 g, 190.0 mmol) was stirred at reflux in triethylorthoformate (60 mL) for 2 h. The reaction was cooled to room temperature and distilled to provide ethyl-N-cyanoimidate (12.5 g, bp=110-112° C./45 mm Hg).* To this imidate (1 mL) was added 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.05 g, 0.2 mmol) and the mixture was heated at 90° C. for 4 h, cooled, diluted with chloroform, filtered, and evaporated. The crude product was purified by reverse phase chromatography to furnish 0.053 g (17%) of the title compound as an off white solid: mp 148-149° C.; ¹H NMR (300 MHz, CDCl₃) δ 9.45 and 9.33 (bd, bs, J=10 Hz, 1H), 8.33 and 8.25 (2d, J≈2 Hz, 1H), 7.46-7.38 (m, 2H), 7.11-7.01 (m, 2H), 5.35 and 5.33 (2s, 2H); HPLC-MS (ESI) m/z 290 (M+H)⁺, 288 (M−H)⁻. *Bridsen, Peter K., and Wang, Xiaodong, Synthesis, 1995, 855-8.

Preparation of N′-[5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-N,N-dimethyl-propionamidine (24)

To a solution of N,N-dimethylpropionamide (0.202 g, 2.0 mmol) in CHCl₃ (2 mL) was added phosphorous oxychloride (POCl₃, 0.066 g, 0.43 mmol) and the mixture was agitated on an orbital shaker at room temperature for 1 h. Triethylamine (0.22 g, 2.2 mmol) and 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.10 g, 0.40 mmol) were added, and the mixture was agitated at 50° C. for 3 h, cooled to room temperature, partitioned between chloroform and water, the phases separated, and the organics evaporated under reduced pressure. Purification by reverse phase chromatography afforded the title compound (0.042 g, 31% yield) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 8.87 (s, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.46-7.40 (m, 2H), 7.07-6.99 (m, 2H), 5.30 (s, 2H), 3.13 (s, 6H), 2.55 (q, J=7.7 Hz, 2H), 1.15 (t, J=7.7 Hz, 3H); HPLC-MS (ESI) m/z 321 (M+H)⁺.

Preparation of N′-(5-Fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethyl-formamidine (25)

To a magnetically stirred solution of 4-amino-5-fluoro-pyrimidin-2-ol* (4.00 g, 31.0 mmol) in DMF (100 mL) was added N,N-dimethylformamide dimethyl acetal (4.00 g, 34.0 mmol). The mixture was stirred at room temperature for 72 h, diluted with diethyl ether (200 mL), and filtered. The solid product was washed with heptane to give the title compound (5.23 g, 92% yield) as a white solid: mp 240-243° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 10.7 (bs, 1H), 8.59 (s, 1H), 7.7 (d, J=5.6 Hz, 1H), 3.18 (s, 3H), 3.06 (s, 3H); HPLC-MS (ESI) m/z 185 (M+H)⁺, 183 (M−H)⁻. *4-amino-5-fluoro-pyrimidin-2-ol can be purchased commercially.

Preparation of Carbonic acid 4-(dimethylamino-methyleneamino)-5-fluoropyrimidin-2-yl ester ethyl ester (26)

To a solution of N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (0.10, 0.54 mmol) in CH₂Cl₂ (2 mL) were added triethylamine (0.20 g, 2.0 mmol) and ethyl chloroformate (0.065 g, 0.60 mmol), and the mixture was agitated on an orbital shaker at room temperature overnight. The reaction was diluted with CH₂Cl₂ and the solution was washed with water, dried over MgSO₄, filtered and evaporated. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether gradient) to yield 0.031 g (22%) of the title compound as a white solid: mp 124-126° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.67 (s, 1H), 8.19 (d, J=2.2 Hz, 1H), 4.35 (q, J=7.14 Hz, 2H), 3.21 (s, 6H), 1.40 (t, J=7.14 Hz, 3H); HPLC-MS (ESI) m/z 258 (M+H)⁺.

Preparation of Benzoic acid 4-(dimethylamino-methyleneamino)-5-fluoropyrimidin-2-yl ester (27)

To a suspension of N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (0.10 g, 0.54 mmol) in pyridine (2 mL) was added benzoyl chloride (0.084 g, 0.60 mmol), and the mixture was agitated on an orbital shaker for 16 h at RT. The reaction mixture was partitioned between EtOAc and saturated aq NaHCO₃, and the organic phase was dried over solid MgSO₄, filtered, and evaporated to give the title compound (0.147 g 94%) as a white solid: mp 136-138° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.69 (s, 1H), 8.27 (d, J=2.4 Hz, 2H), 8.25-8.20 (m, 2H), 7.69-7.63 (m, 1H), 7.56-7.49 (m, 2H), 3.23 (s, 3H), 3.20 (s, 3H); HPLC-MS (ESI) m/z 289 (M+H)⁺.

Preparation of Benzenesulfonic acid 4-(dimethylamino-methyleneamino)-5-fluoro-pyrimidin-2-yl ester (28)

To a suspension of N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (0.10 g, 0.54 mmol) in pyridine (2 mL) was added benzene sulfonyl chloride (0.106 g, 0.60 mmol) and the mixture was agitated on an orbital shaker for 16 h at room temperature. The reaction mixture was partitioned between EtOAc and saturated aq NaHCO₃, and the organic phase was dried over solid MgSO₄, filtered, and concentrated under reduced pressure. Purification by reverse phase chromatography (H₂O/MeCN gradient) afforded the title compound (0.089 g, 46% yield) as a white solid: mp 124-125° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.54 (s, 1H), 8.12-8.07 (m, 3H), 7.73-7.66 (m, 1H), 7.62-7.56 (m, 2H), 3.21 (s, 6H); HPLC-MS (ESI) m/z 325 (M+H)⁺.

Preparation of Benzenesulfonic acid 4-amino-5-fluoropyrimidin-2-yl ester (29)

To a solution of 10% 1N HCl in doxane (3 mL) was added benzenesulfonic acid 4-(dimethylamino-methyleneamino)-5-fluoropyrimidin-2-yl ester (0.090, 0.3 mmol) and the mixture was agitated on an orbital shaker at room temperature for 1.5 h. The solvent was removed by evaporation and the residue was dissolved in a 1:1 solution of dioxane and water (2.5 mL) and treated with saturated aq NaHCO₃ (0.5 mL). After 16 h, the reaction mixture was partitioned between EtOAc and water and the organic phase was dried over Na₂SO₄, filtered, and the solvent evaporated to yield the title compound (0.059 g, 79% yield) as a white solid: mp 139-141° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.05-8.00 (m, 3H), 7.90-7.75 (m, 3H), 7.70-7.63 (m, 2H); HPLC-MS (ESI) m/z 268 (M−H)⁻, 270 (M+H)⁺.

Preparation of Benzenesulfonic acid 4-amino-5-fluoropyrimidin-2-yl ester (29)

To a suspension of 4-amino-5-fluoro-pyrimidin-2-ol (0.177 g, 1.4 mmol) in pyridine (5 mL) was added benzene sulfonyl chloride (0.284 g, 1.6 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness and the crude material purified by reverse phase chromatography to yield the title compound (0.106 g, 29% yield) as a white solid: mp 145-146° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.05-8.00 (m, 3H), 7.9-7.75 (m, 3H), 7.70-7.63 (m, 2H); HPLC-MS (ESI) m/z 270 (M+H)⁺, 268 (M−H)⁻.

Preparation of (2-Fluorobenzyl)-[5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]amine (30)

A) A magnetically stirred solution of 2,4-dichloro-5-fluoropyrimidine* (0.105 g, 0.63 mmol) in 5 mL of dry THF was treated with 2-fluorobenzylamine (0.085 g, 0.68 mmol) and excess triethylamine, and the resulting mixture was heated at 80° C. for 5 h. The reaction mixture was partitioned between CH₂Cl₂ and dilute HCl, and the organic phase was washed with brine, dried over Na₂SO₄, and filtered. The solvent was removed under reduced pressure to yield 0.157 g (97%) of the title compound as a yellow solid: mp 117-118° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.90 (d, J=2.6, 1H), 7.47-7.27 (m, 2H), 7.21-7.01 (m, 2H), 5.54 (s, 1H), 4.76 (d, J=5.9, 2H); MS (ESI) m/z 256 (M+H)⁺. *2,4-Dichloro-5-fluoropyrimidine can be purchased commercially.

B) A solution of (2-chloro-5-fluoropyrimidin-4-yl)-(2-fluorobenzyl)amine* (0.103 g, 0.40 mmol) in 5 mL of dry THF was treated with 4-fluorobenzylalcohol (0.062 g, 0.49 mmol) and a 1.0 M solution of KO^(t)Bu in ^(t)BuOH (0.4 mL, 0.4 mmol). The mixture was heated at 80° C. in a sealed vial for 18 h, partitioned between CH₂Cl₂ and water, and the organic phase was washed with brine, dried over Na₂SO₄, and filtered. The solvent was removed under reduced pressure and the residue purified by flash column chromatography (SiO₂, 10→20% EtOAc/petroleum ether) to yield the title compound (0.157 g, 42%) as a white solid: mp 83-84° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J=2.8, 1H), 7.45-7.27 (m, 5H), 7.15-6.96 (m, 5H), 5.37 (br s, 1H), 5.29 (s, 3H), 4.74 (d, J=5.9, 3H); MS (ESI) m/z 346 (M+H)⁺. *Singh, R.; Argade, A.; Payan, D. G.; Clough, J.; Keim, H.; Sylvain, C.; Li, H.; Bhamidipati, S., WO 2004014382 A1 20040219

Preparation of 5-Fluoro-2-(3-methoxybenzyloxy)-4-(1-(4-methoxyphenyl)-hydrazinyl)pyrimidine (31)

A) A 1.0 M solution of t-BuOK in t-BuOH (66 mL, 66 mmol) was added to a mixture of 2,4-dichloro-5-fluoropyrimidine (5.04 g, 30.1 mmol) and 3-methoxybenzyl alcohol (7.8 mL, 62.8 mmol) in a 250 mL round bottom flask. A significant exotherm was observed and the resulting mixture was stirred at room temperature for 2 h. The reaction was diluted with EtOAc (100 mL) and washed with brine (50 mL×2). The organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. Crystallization from hot EtOH provided a material which was collected on a fritted funnel and rinsed with ice-cold EtOH to provide the title compound (7.94 g, 71%) as a white solid: mp 81-83° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.10 (d, J=2.3 Hz, 1H), 7.29 (m, 2H), 7.02 (m, 4H), 6.87 (dt, J=2.2, 7.8 Hz, 2H), 5.44 (s, 2H), 5.35 (s, 2H), 3.82 (s, 3H), 3.82 (s, 3H); MS (ESI) m/z 371 (M+H)⁺.

B) A solution of 2.0 N KOH in water (85 mL, 170 mmol) was added to a mixture of 5-fluoro-2,4-bis(3-methoxybenzyloxy)pyrimidine (7.9 g, 21.3 mmol) and EtOH (21 mL) in a 500 mL round bottom flask. A reflux condenser was attached, and the reaction was heated at 95° C. for 16 h. After cooling to room temperature, the reaction mixture was washed with Et₂O (2×50 mL), and then acidified with 1 N HCl to pH 3. The resulting solid material was collected on a fritted funnel. Subsequent extraction with excess EtOAC, and concentration under reduced pressure provided the title compound (3.63 g, 68%) as a white solid: mp 136-139; ¹H NMR (300 MHz, DMSO-d₆) δ 12.97 (br s, 1H), 7.87 (d, J=3.7 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.00 (m, 2H), 6.91 (dd, J=1.8, 8.0 Hz, 1H), 5.29 (s, 2H), 3.74 (s, 3H); MS (ESI) m/z 251 (M+H)⁺.

C) An oven-dried 100 mL Schlenk flask was charged with 5-fluoro-2-(3-methoxybenzyloxy)pyrimidin-4-ol (3.63 g, 14.5 mmol) and N,N-dimethylaniline (3.7 mL, 29.2 mL). Phosphorous oxychloride (POCl₃, 40 mL, 429 mmol) was added, and resulting solution was heated to 95° C. under nitrogen. After 2 h, the reaction was cooled to room temperature and concentrated to constant volume under reduced pressure at 50° C. The remaining residue was diluted with Et₂O (50 mL) and washed with 1 N HCl (2×50 mL). Concentration at reduced pressure provided a solid, which was washed with water and collected by vacuum filtration. The title compound (4.09 g, 105%) was isolated as a white solid: mp 96-100° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.81 (d, J=0.8 Hz, 1H), 7.30 (t, J=8.1 Hz, 1H), 7.02 (m, 2H), 6.91 (dd, J=2.3, 8.3 Hz, 1H), 5.34 (s, 2H), 3.75 (s, 3H); MS (ESI) m/z 269 (M+H)⁺.

D) To a mixture of 4-chloro-2-(3-methoxybenzyl)-5-fluoropyrimidine (0.153 g, 0.568 mmol) and 4-methoxyphenyl-hydrazine hydrochloride (0.324 g, 1.85 mmol) in ethanol (5 mL) was added triethylamine (0.272, 2.69 mmol) and the mixture was heated to 50° C. for 16 h. The reaction was cooled to room temperature and diluted with Et₂O (50 mL). The Et₂O solution was washed with water (2×50 mL), dried over MgSO₄, filtered, and concentrated. The residue was triturated with Et₂O to obtain 5-fluoro-2-(3-methoxy-benzyloxy)-4-(1-(4-methoxyphenyl)hydrazinyl)pyrimidine (0.113 g, 54% yield) as a white solid: mp 121-123.5° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.02 (d, J=5.4 Hz, 1H), 7.28 (t, J=8.1 Hz, 1H), 7.22 (d, J=8.5 Hz, 2H), 6.99-6.93 (m, 2H), 6.93-6.85 (m, 3H), 5.25 (s, 2H), 3.75 (s, 3H), 3.74 (s, 3H); MS (ESI) m/z 371 (M+H)⁺, 354 (M-NH₂)⁻.

Preparation of O-Allyl-N-(5-fluoro-2-(3-methoxybenzyloxy)pyrimidin-4-yl)hydroxylamine (32)

To a mixture of 4-chloro-2-(3-methoxybenzyl)-5-fluoropyrimidine (0.151 g, 0.558 mmol) and O-allyl hydroxylamine hydrochloride (0.201 g, 1.83 mmol) in 5:1 MeOH:CH₃CN (5 mL) was added triethylamine (0.273 g, 2.70 mmol) and the mixture was heated at 50° C. for 18 h. The reaction was cooled to room temperature and diluted with Et₂O (50 mL). The organic solution was washed with water (2×50 mL), dried over MgSO₄, filtered, and concentrated. Purification by flash chromatography (SiO₂, 17%-->50% EtOAc/hexane) afforded O-allyl-N-(5-fluoro-2-(3-methoxybenzyloxy)-pyrimidin-4-yl)hydroxylamine (0.113 g, 66% yield) as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆) δ 10.94 (broad singlet, 1H), 7.94 (broad singlet, 1H), 7.28 (t, J=8.0 Hz, 1H), 6.95-7.03 (m, 2H), 6.88 (dd, J=2.5, 7.9 Hz, 1H), 5.97 (tdd, J=5.8, 10.6, 17.0 Hz, 1H), 5.32 (dd, J=1.5, 17.4 Hz, 1H), 5.24 (s, 2H), 5.22 (dd, J=1.2, 10.6 Hz, 1H), 4.39 (d, J=6.0 Hz, 2H), 3.74 (s, 3H); MS (ESI) m/z 306 (M+H)⁺, 304 (M−H)⁻.

Preparation of 1-[2-(3-Cyanobenzyloxy)-5-fluoropyrimidin-4-yl]-3-(2-fluorobenzyl)urea (34)

To a magnetically stirred mixture of 3-(4-amino-5-fluoropyrimidin-2-yloxymethyl)-benzonitrile (0.075 g, 0.31 mmol) and 2-fluorobenzylisocyanate (0.59 mL, 0.46 mmol) in dry DMF (1.5 mL) was added LiHMDS (1.0 M in THF, 0.31 ml, 0.30 mmol). The vial was capped and the mixture stirred at room temperature for 8 h. Saturated aq. NH₄Cl (3 ml) was added and the mixture was stirred for 4 h. The heterogeneous mixture was filtered, and the solid was washed with hot water, washed with E₂O, and then dried under vacuum to give the title compound (0.075 g, 62%) as a white solid: mp 177-178° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (s, 1H), 8.90 (t, J=5.7 Hz, 1H), 8.37 (d, J=2.8 Hz, 1H), 7.85 (br s, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.42-7.38 (m, 1H), 7.35-7.29 (m, 1H), 7.20-7.14 (m, 2H), 5.33 (s, 2H), 4.49 (d, J=5.8 Hz, 2H); HPLC-MS (ESI) m/z 396.3 (M+H)⁺, 394.3 (M−H)⁻.

Preparation of 1-[5-Fluoro-2-(3-methoxybenzyloxy)pyrimidin-4-yl](3′-propyl carbamoyl)-3-propyl-urea (36)

To a magnetically stirred mixture of 5-fluoro-2-(3-methoxybenzyloxy)pyrimidin-4-ylamine (0.075 g, 0.30 mmol) and propylisocyanate (0.057 mL, 0.60 mmol) in dry DMF (1.5 mL) was added LiHMDS (1.0 M in THF, 0.60 ml, 0.60 mmol). The vial was capped and the reaction was stirred at room temperature for 8 h. The solvent was evaporated under reduced pressure and the crude material was purified by reverse-phase chromatography to give the title compound (0.043 g, 10%) as a tan solid: mp 75-78° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.34 (s, 1H), 8.49 (s, 1H), 7.89 (s, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.05-7.01 (m, 2H), 6.90 (dd, J=6.9 Hz, J=2.5 Hz, 1H), 5.30 (s, 2H), 3.75 (s, 3H), 3.74-3.68 (m, 2H), 3.15-3.10 (m, 2H), 1.58-1.44 (m, 4H), 0.89-0.85 (m, 6H); HPLC-MS (ESI) m/z 420.4 (M+H)⁺, 418.4 (M−H)⁻.

Preparation of 1-[2-(3-Cyanobenzyloxy)-5-fluoropyrimidin-4-yl]-3-propylthiourea (37)

To a magnetically stirred mixture of 3-(4-amino-5-fluoropyrimidin-2-yloxymethyl)-benzonitrile (0.075 g, 0.31 mmol) and propylisothiocyanate (0.047 mL, 0.46 mmol) in dry DMF (1.5 mL) was added LiHMDS (1.0 M in THF, 0.31 ml, 0.31 mmol). The vial was capped and reaction was stirred for 8 h. Saturated aq NH₄Cl (3 ml) was added to the vial and the mixture was stirred for 4 h. The heterogeneous mixture was filtered and the solid was washed with hot water, washed with hexanes, and dried under vacuum to give the title compound (0.055 g, 52%) as a pale-yellow solid: mp 163-165° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H), 10.38 (s, 1H), 8.47 (d, J=2.7 Hz, 1H), 7.90 (s, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 5.42 (s, 2H), 3.55 (dd, J=12.4, 6.8 Hz, 2H), 1.65-1.59 (m, 2H), 0.95 (t, J=7.5 Hz, 3H): HPLC-MS (ESI) m/z 346.3 (M+H)⁺, 344.2 (M−H)⁻.

Preparation of N-[5-Fluoro-2-(4-methylbenzyloxy)pyrimidin-4-yl]methanesulfonamide (38)

To a solution of 5-fluoro-2-(4-methylbenzyloxy)pyrimidin-4-ylamine (0.100 g, 0.43 mmol) in anhydrous THF (4 mL) was added LiHMDS (1.07 mL of 1.0M, 1.07 mmol) dropwise at room temperature, and the resulting orange solution was stirred for 20 min. Methanesulfonyl chloride (0.108 g, 0.94 mmol) was added in one portion and the turbid, light orange solution was stirred for 60 min. The reaction was quenched with brine (5 mL) and the THF phase was separated. The aq. phase was extracted w/EtOAc (5 mL), and the organics were combined, dried over Na₂SO₄, filtered, and concentrated to an orange gummy residue. The residue was purified by flash chromatography (SiO₂, 0→100% EtOac/hexanes) to give 0.034 g (26%) of the title compound as a white solid: mp 145-148° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.33 (d, J=7.9 Hz, 2H), 7.17 (d, J=7.9 Hz, 2H), 5.35 (s, 2H), 3.37 (s, 3H), 2.35 (s, 3H); HPLC-MS (ESI) m/z 312 (M+H)⁺, 310 (M−H)⁻.

Preparation of N-[5-Fluoro-2-(4-fluorobenzyloxy)-pyrimidin-4-yl]-S-(2-nitrophenyl)-thiohydroxylamine (39)

To a solution of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.05 g, 0.2 mmol) and a 1.0 M solution of t-BuOK in t-BuOH (1.0 mL, 1.0 mmol) was added nitrobenzene-sulfenyl chloride (0.044 g, 0.23 mmol) in one portion, and the resulting brown solution was stirred for 60 min. The reaction was diluted with water (2 mL) and neutralized to pH 7 with 1N HCl. The aq. phase was extracted with EtOAc (5 mL), and the organics were combined, dried over Na₂SO₄, filtered, and concentrated. The crude material was purified by reverse phase chromatography to yield the title compound (0.020 g, 26%) as a yellow solid: mp 184° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.36 (d, J=7.25 Hz, 1H), 8.09 (d, J=2.3 Hz, 1H), 7.59 (m, 1H), 7.36 (m 2H), 7.29 (m, 2H), 6.88 (m, 2H), 6.23 (bs, 1H), 5.19 (s, 2H); HPLC-MS (ESI) m/z 391 (M+H)⁺, 389 (M−H)⁻.

Preparation of Benzenesulfonic acid 4-acetylamino-5-fluoro-pyrimidin-2-yl ester (40)

N-(5-Fluoro-2-hydroxypyrimidin-4-yl)-acetamide* (200 mg, 1.17 mmol) was suspended in pyridine (5 mL) and stirred at ambient temperature. To the stirred suspension was added benzenesulfonyl chloride (226 mg, 1.29 mmol) and agitation was continued for 16 hours. The solvent was evaporated under a stream of nitrogen and the residue was suspended in dichloromethane (2-3 mL), placed directly onto a silica gel column, and eluted with ethyl acetate in petroleum ether (0-50% gradient) to isolate 180 mg, 0.58 mmol (49%) of the title compound as a white solid: mp 142-143° C.; ¹H NMR (DMSO-d₆) δ 10.96 (s, 1H), 8.67 (d, J=2.6 Hz, 1H), 8.12-8.06 (m, 2H), 7.86-7.79 (m, 1H), 7.73-7.65 (m, 2H), 2.98 (s, 3H); HPLC-MS (ESI) m/z 312 (M+H)⁺, 310 (M−H)⁻. *N-(5-Fluoro-2-hydroxypyrimidin-4-yl)-acetamide can be prepared through known literature methods. 1. Duschinsky, R., Fells, E., Hoffer, M. U.S. Pat. No. 3,309,359

Preparation of 2,2-Dimethylpropionic acid 4-(dimethylamino-methyleneamino)-5-fluoro-pyrimidin-2-yloxymethyl ester (41)

N′-(5-Fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), cesium carbonate (196 mg, 0.60 mmol), and chloromethyl pivalate (90 mg, 0.6 mmol) were shaken together in DMF (3 mL) at ambient temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water, dried over magnesium sulfate, filtered and evaporated to yield a colorless oil which was treated with diethyl ether (3-4 mL) to produce a solid. The solid was removed and the ether solution was placed onto a silica gel column and eluted with ethyl acetate in petroleum ether (0-50% gradient) to isolate 14 mg, 0.05 mmol (9%) of the title compound as a white solid: mp 86-88° C.; ¹H NMR (CDCl₃) δ 8.73 (s, 1H), 8.06 (d, J=2.6 Hz, 1H), 6.04 (s, 2H), 3.20 (s, 3H), 3.18 (s, 3H), 1.16 (s, 9H); HPLC-MS (ESI) m/z 299 (M+H)⁺.

Preparation of N′-(5-Fluoro-2-methoxymethoxypyrimidin-4-yl)-N,N-dimethyl-formamidine (42)

N′-(5-Fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), cesium carbonate (196 mg, 0.60 mmol), and bromomethyl methyl ether (75 mg, 0.6 mmol) were shaken together in DMF (3 mL) at ambient temperature for 4 hours. The reaction mixture was partitioned between ethyl acetate and water, dried over magnesium sulfate, filtered and evaporated to yield a colorless oil which was placed directly onto a silica gel column and eluted with ethyl acetate in petroleum ether (0-80% gradient) to isolate 23 mg, 0.1 mmol (19%) of the title compound as a colorless oil: ¹H NMR (CDCl₃) δ 8.66 (s, 1H), 8.05 (d, J=2.6 Hz, 1H), 5.46 (s, 2H), 3.53 (s, 3H), 3.17 (s, 3H), 3.16 (s, 3H); HPLC-MS (ESI) m/z 229 (M+H)⁺.

Preparation of [5-Fluoro-2-(3-methoxybenzyloxy)pyrimidin-4-yl]sulfamide (43)

To a magnetically stirred solution of 4-chloro-5-fluoro-2-(3-methoxybenzyloxy)pyrimidine* (1.3 g, 4.84 mmol) in dry DMF (5 mL) was added a pre-mixed suspension of 60% NaH (0.45 g, 10.65 mmol) and sulfamide (0.93 g, 9.68 mmol) in dry DMF (5 mL). The resulting off-white suspension was stirred at room temperature for 72 hrs. The orange suspension was then heated to 50° C. for 48 hours and cooled to room temperature. The reaction mixture was partitioned between ethyl acetate and brine solution. The organic extract was dried over Na₂SO₄, filtered, and evaporated. The crude material was purified by column chromatography on normal phase silica using a gradient of EtOAc/Hex and reverse phase using a gradient of H₂O/CH₃CN to yield [5-fluoro-2-(3-methoxybenzyloxy)pyrimidin-4-yl]sulfamide (115 mg, 7.2% yield) as a white solid: mp 126-130° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.01 (d, J=3.63 Hz, 1H), 7.25 (m, 1H), 7.01 (m, 2H), 6.88 (m, 1H), 5.37 (s, 2H), 3.78 (s, 3H); MS (ESI) m/z 326.9 (M−H) *The 4-chloro-5-fluoro-2-(3-methoxybenzyloxy)pyrimidine intermediate was prepared as described in the synthesis of 31.

Preparation of 5-Fluoro-4-hydrazinyl-2-(3-methoxybenzyloxy)pyrimidine (44)

A 125 mL Erlenmeyer flask was charged with 4-chloro-5-fluoro-2-(3-methoxybenzyl-oxy)pyrimidine (1.50 g, 5.58 mmol) and EtOH (50 mL). Hydrazine monohydrate (900 μL, 18.5 mmol) was added, and the resulting mixture was allowed to stir at room temperature. After 22 h, the reaction was transferred to a 500 mL Erlenmeyer flask and diluted with water (200 mL), whereupon a white solid began to precipitate from solution. After stirring for 7 h, solid product was collected in a fritted funnel and rinsed with excess water. After drying on the frit, the title compound was obtained (1.23 g, 83%) as a white solid: mp 103-106° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.92 (bs, 1H), 7.86 (d, J=3.6 Hz, 1H), 7.27 (t, J=8.1 Hz, 1H), 6.94-7.01 (m, 2H), 6.87 (dd, J=2.4, 7.9 Hz, 1H), 5.24 (s, 2H), 4.46 (bs, 2H), 3.74 (s, 3H); MS (ESI) m/z 265.2 (M+H)⁺, 263.2 (M−H)⁻.

Preparation of (E)-5-Fluoro-2-(3-methoxybenzyloxy)-4-(2-(thiophen-2-ylmethylene)-hydrazinyl)pyrimidine(45)

A 20 mL vial was charged with 5-fluoro-4-hydrazinyl-2-(3-methoxybenzyloxy)-pyrimidine (74.7 mg, 0.283 mmol), EtOH (2 mL), thiophene-2-carbaldehyde (26 μL, 0.284 mmol) and 1 M HCl in Et₂O (14 μL, 0.014 mmol) and heated at 50° C. on shaker. After 90 minutes, the reaction was cooled to room temperature concentrated on high vacuum to provide the title compound (77.8 mg, 77%) as a yellow solid: mp 136-139° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 11.46 (bs, 1H), 8.50 (bs, 1H), 8.16 (d, J=3.6 Hz, 1H), 7.64 (d, J=5.0 Hz, 1H), 7.41 (d, J=3.4 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.12 (dd, J=3.8, 4.8 Hz, 1H), 7.04 (m, 2H), 6.88 (dd, J=2.4, 8.3 Hz, 1H), 5.27 (s, 2H), 3.73 (s, 3H); MS (ESI) m/z 359.2 (M+H)⁺, 357.2 (M−H)⁻.

Preparation of 2-(Benzyloxy)-4-[(dimethyl-λ⁴-sulfanylidene)amino]-5-fluoropyrimidine (47)

A 10 mL oven-dried Schlenk flask was charged with 2-(benzyloxy)-5-fluoropyrimidin-4-amine (101 mg, 0.462 mmol), CH₂Cl₂ (2 mL), and dimethylsulfide (75.0 μL, 1.02 mmol) and was cooled to 0° C. in an ice bath. N-Chlorosuccinimide (122 mg, 0.914 mmol) was added and the resulting mixture was allowed to stir at 0° C. for 45 minutes, and then at room temperature for 30 minutes. A solution of NaOMe in MeOH (25%, 360 μL, 1.35 mmol) was added. After 20 minutes, the reaction was quenched with water (3 mL) and allowed to stir for 1 hour. The crude reaction mixture was then diluted with CH₂Cl₂ and washed with water (50 mL×2), dried over anhydrous Na₂SO₄, filtered, and concentrated by rotary evaporation and then on high vacuum to give the title compound (120 mg, 93%) as an off white solid: mp 125-129° C.; ¹H NMR (300 MHz, DMSO-d₆): δ 7.70 (d, J=3.9 Hz, 1H), 7.25-7.44 (m, 5H), 5.21 (s, 2H), 2.75 (s, 6H); MS (ESI) m/z 281.1 (M+H)⁺. *Yamamoto, Y.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 4128-4129.

Preparation of 1-[5-Fluoro-2-(4-methylbenzyloxy)-pyrimidin-4-yl]-2,3-dipropyl-isothiourea (49)

To a magnetically stirred solution of 1-[5-fluoro-2-(4-methyl-benzyloxy)-pyrimidin-4-yl]-3-propyl-thiourea (0.50 g, 1.40 mmol) in CH₃CN (4 mL), was added potassium carbonate (0.20 g, 1.40 mmol) at room temperature and the mixture was stirred for 20 min. N-propylbromide (0.19 g, 1.40 mmol) was added at room temperature and the resulting mixture stirred for 15 h. The reaction mixture was diluted with H₂O and extracted with CH₂Cl₂ (3×20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and the solvent evaporated. The crude mixture was purified on silica (EtOAc/hexanes gradient) and evaporation of the product fractions gave 0.335 g (63%) of 1-[5-fluoro-2-(4-methyl-benzyloxy)-pyrimidin-4-yl]-2,3-dipropyl-isothiourea as a pale yellow viscous liquid: ¹H NMR (300 MHz, CDCl₃) δ 10.56 (bs, 1H), 8.09 (d, J=2.6 Hz, 1H), 7.31 (m, 2H), 7.24 (m, 2H), 5.28 (s, 2H), 3.28 (dd, J=13.6, 6.5 Hz, 4H), 2.36 (s, 3H), 1.62 (m, 4H), 1.0 (t, J=7.4 Hz, 4H); HPLC-MS (ESI) m/z 377 (M+H)⁺.

Preparation of O-(4-Amino-5-fluoropyrimidin-2-yl)-t-butyl N-methyl-N-hydroxycarbamate (50)

In a 2 dram screw cap vial, a solution of 4-amino-2-chloro-5-fluoropyrimidine (0.1 g, 0.68 mmol) and t-butyl N-methyl-N-hydroxycarbamate* (0.11 g, 0.75 mmol) was treated with a 1.0 M solution of t-BuOK in t-BuOH (1.0 mL, 1.0 mmol) in one portion, and the resulting yellow solution was heated at 100° C. and shaken for 24 h. The reaction mixture was cooled, extracted with EtOAc (3×5 mL), and the solvent evaporated. The crude mixture was purified via reverse phase chromatography to yield 0.10 g (56.9%) of the title compound as yellow solid: mp 123-125° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.96 (d, J=2.3 Hz, 1H), 5.26 (bs, 2H), 3.32 (s, 3H), 1.43 (s, 9H); MS (ESI) m/z 259 (M+H)⁺. *t-butyl N-methyl-N-hydroxycarbamate can be prepared through known literature methods:

1. Carrasco, M. R.; Brown, R, T.; Serafimova, I. M.; Silva O. J. Org. Chem., 2003, 68 (1), 195.

Preparation of O-ethyl 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylcarbamothioate (51)

5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-amine (300 mg, 1.26 mmol) was stirred in chloroform (25 mL) and water (12 mL). Sodium bicarbonate (870 mg, 10.12 mmol) was added followed by dropwise addition of thiophosgene (218 mg, 1.9 mmol). The reaction mixture was stirred at room temperature for 16 hours, then diluted with chloroform (20 mL) and the phases were separated. The organic extract was dried over sodium sulfate, filtered, and concentrated by rotary evaporation to ⅓ volume. To this chloroform solution of crude isothiocyanate was added abs. ethanol (10 mL) and the mixture was heated in a sealed tube for 1 h. The reaction mixture was cooled to room temperature, concentrated and purified by flash chromatography on silica, to give 45 mg (11%) of O-ethyl 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylcarbamothioate as a pale yellow solid: mp 109-119° C.; ¹H NMR (CDCl₃) δ 8.30 (bs, 2H), 7.44 (m, 2H), 7.06 (m, 2H), 5.36 (s, 2H), 4.66 (q, J=6 Hz, 2H), 1.45 (t, J=6 Hz, 3H); HPLC-MS (ESI): m/z 326 (ES⁺).

Preparation of N-(5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl)ethanethioamide (53)

N-(5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl)acetamide (50 mg, 0.42 mmol) was stirred in a Biotage Initiator® microwave vessel with 1,2-dichloroethane (3 mL) and Lawesson's reagent (170 mg, 0.42 mmol). The vessel was heated in a Biotage Initiator® microwave to 100° C. for 5 minutes then cooled room temperature, filtered, and diluted with CH₂Cl₂. The reaction mixture was then washed brine, and the layers were separated. The organic extract was dried onto silica and purified by flash chromatography. The product-containing fractions were then evaporated to dryness and purified again by reverse-phase HPLC to give 4 mg of N-(5-fluoro-2-(4-fluorobenzyl-oxy)pyrimidin-4-yl)ethanethioamide (4%) as a yellow glass: ¹H NMR (CDCl₃) δ 9.34 (b, 1H), 8.29 (d, J=3 Hz, 1H), 7.41 (m, 2H), 7.06 (m, 2H), 5.33 (s, 2H), 3.13 (s, 3H); HPLC-MS (ESI): m/z 294 (ES⁻).

Preparation of 1-(5-Fluoro-2-hydroxypyrimidin-4-yl)-3-(2-methoxyphenyl)urea (954)

To a magnetically stirred mixture of 4-amino-2-hydroxy-5-fluoropyrimidine (150 mg, 1.16 mmol) in dry DMF (3.5 mL) was added 2-methoxyphenyl isocyanate (170 μL, 1.28 mmol) and the white suspension was allowed to stir at room temperature for 60 min. The mixture was heated to 55° C. for 3 h, and then allowed to stir at room temperature overnight. The precipitate was collected by vacuum filtration and washed with Et₂O (10×3 mL) to give a solid material, which was air dried for 1 h to give 1-(5-fluoro-2-hydroxypyrimidin-4-yl)-3-(2-methoxyphenyl)urea (269 mg, 83%) as a white solid: mp 247-250° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 12.24 (bs, 1H), 11.31 (bs, 1H), 10.16 (bs, 1H), 8.14 (d, J=7.91 Hz, 1H) 8.0 (d, J=5.6, 1H), 7.03-6.99 (m, 2H), 6.95-6.88 (m, 1H), 3.87 (s, 3H) MS (ESI) m/z 276.9 (M−H)⁻.

Preparation of N-(5-Fluoro-2-(4-methylbenzyloxy)pyrimidin-4-yl)-4-methylbenzenesulfonamide (955)

To a magnetically stirred solution of 5-fluoro-2-(4-methylbenzyloxy)pyrimidin-4-amine (200 mg, 0.857 mmol) in sure seal THF (4 mL) was added 1M lithium bis(trimethylsilyl)amide (LiHMDS) solution in THF (1.28 mL, 1.28 mmol) causing a slight exotherm. After stirring for 5 min, p-toluenesulfonyl chloride (196.65 mg, 1.028 mmol) was added and after 10 min the orange solution turned light yellow and turbid. The mixture was stirred at room temperature for 4 h. The solvent was removed in vacuo and the resulting viscous gold oil was diluted in EtOAc (50 mL), poured into a separatory funnel containing EtOAc (75 mL) and washed with 1N HCl aqueous solution (4×75 mL) followed by brine solution (1×100 mL). The organic extract was dried over Na₂SO₄, filtered, and evaporated. To the crude oil material was added distilled water (150 mL) and the resulting mixture was vigorously stirred at room temperature over 72 h forming an off-white solid. The solid was collected by vacuum filtration and air dried for 1 hour followed by drying under vacuum for 24 hours. The white solid was then suspended in Et₂O (2 mL) for 1 h, then collected by vacuum filtration washed with Et₂O (1×1 mL), and air dried for 1 h to yield N-(5-fluoro-2-(4-methylbenzyloxy)pyrimidin-4-yl)-4-methylbenzenesulfonamide (150 mg, 45.2% yield) as a white solid: mp 120-122° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (d, J=2.9 Hz, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.23 Hz, 2H), 7.16 (d, J=7.92 Hz, 2H), 5.08 (s, 2H), 2.33 (s, 3H), 2.29 (s, 3H) MS (ESI) m/z 386.3 (M−H)

Preparation of N-(5-Fluoro-2-hydroxypyrimidin-4-yl)benzenesulfonamide (956)

A) To a magnetically stirred solution of 5-fluoro-2-(2-methoxybenzyloxy)pyrimidin-4-amine (500 mg, 2.01 mmol) in dry THF (10 mL) was added 1M LiHMDS solution in THF (3.21 mL, 3.21 mmol) causing a slight exotherm. After stirring for 5 min, benzenesulfonyl chloride (0.346 mL, 2.71 mmol) was added and after 10 min the orange solution turned light orange and turbid. The mixture was stirred at room temperature for 5 h. The solvent was removed in vacuo and the resulting viscous gold oil was diluted in EtOAc (10 mL), poured into a separatory funnel containing EtOAc (100 mL) and washed with 1N HCl aqueous solution (4×50 mL) and brine solution (1×50 mL). The organic extract was dried over Na₂SO₄, filtered, and evaporated to yield N-(5-fluoro-2-(2-methoxybenzyloxy)pyrimidin-4-yl)benzenesulfonamide (714 mg, 91% yield) as a light tan solid. MS (ESI) m/z 387.99 (M−H)

B) The solid N-(5-fluoro-2-(2-methoxybenzyloxy)pyrimidin-4-yl)benzenesulfonamide (714 mg, 1.83 mmol) was dissolved in dichloromethane (10 mL) followed by the addition of trifluoroacetic acid (1.0 mL, 13.5 mmol) and allowed to stir at room temperature for 1 h. The solvent was removed in vacuo and the resulting residue was dissolved in dichloromethane:methanol in a 10:1 ratio. The product was purified by column chromatography (dichloromethane/methanol gradient) to yield N-(5-fluoro-2-hydroxypyrimidin-4-yl)benzenesulfonamide (251 mg, 51% yield) as a white solid: mp 221-223° C.; ¹H NMR (300 MHz,) δ 11.57 (bs, 1H), 11.11 (bs, 1H), 8.04 (d, J=6.1 Hz, 1H), 7.94-7.84 (m, 2H), 7.71-7.51 (m, 3H).

Preparation of 4-(Benzylmethylamino)-5-fluoropyrimidin-2-ol (957)

A) To a suspension of 2,4-dichloro-5-fluoropyrimidine (0.30 g, 1.80 mmol) in dioxane (3.6 mL) were added N-ethyl-N-isopropylpropan-2-amine (0.23 g, 1.80 mmol) and N-methyl-1-phenylmethanamine (0.24 g, 1.98 mmol), and the resulting mixture was stirred at room temperature for 16 h. The reaction was diluted with EtOAc (15 mL) and the resulting solution was washed with H₂O (2×5 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated to a light yellow oil which was purified by flash chromatography (40 g SiO₂, EtOAc/Hexanes gradient) to give a colorless oil which solidified upon cooling. The solid was dried under high vacuum at 23° C. for 16 h to give N-benzyl-2-chloro-5-fluoro-N-methylpyrimidin-4-amine (0.34 g, 76%) as a white solid: mp 47-49° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.18 (d, J=6.4, 1H), 7.43-7.23 (m, 5H), 4.82 (s, 2H), 3.17 (d, J=3.3, 3H); MS (EI) m/z 251 (M)⁺.

B) To a suspension of N-benzyl-2-chloro-5-fluoro-N-methylpyrimidin-4-amine (0.075 g, 0.30 mmol) in dioxane/H₂O (1:1, 2 mL total volume) was added KOH (0.17 g, 3.0 mmol) and the mixture was warmed to 100° C. and stirred for 72 h. The reaction was diluted with H₂O (5 mL) and the pH was adjusted to 7 with 2 N HCl. The resulting white precipitate was collected by vacuum filtration, but the majority of the product remained in the aqueous phase. The solid and filtrate were combined and the solvent was removed by azeotropic distillation with CH₃CN on the rotary evaporator. The residue was dissolved/suspended in CH₂Cl₂ (25 mL), adsorbed onto Celite (3.0 g) and purified by flash chromatography (24 g SiO₂, MeOH/CH₂Cl₂ gradient) to give 4-(benzylmethylamino)-5-fluoropyrimidin-2-ol (0.016 g, 23%) as a white solid: mp 175-178° C.; ¹H NMR (300 MHz, CDCl₃) δ 12.72 (s, 1H), 7.42-7.14 (m, 6H), 4.88 (s, 2H), 3.20 (d, J=3.2, 3H); MS (ESI) m/z 235 (M+2)⁺, m/z 232 (M−H)⁻.

Preparation of 2-Benzyloxy-5-fluoro-pyrimidin-4-yl)-(3-trifluoromethyl-phenyl)-diazene (958)

A) A 25 mL vial was charged with 2-(benzyloxy)-4-chloro-5-fluoropyrimidine (153 mg, 0.639 mmol), (3-(trifluoromethyl)phenyl)hydrazine (338 mg, 1.92 mmol), ethanol (8 mL), and triethylamine (140 μL, 1.00 mmol). The resulting yellow solution was heated at 50° C. on an orbital shaker for 16 h. The crude material was then diluted with Et₂O (100 mL) and washed with 1.0 M aqueous NaH₂PO₄ (50 mL) and then water (50 mL). The organic phase was dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (EtOAc/hexane gradient) to afford 2-(benzyloxy)-5-fluoro-4-(2-(3-(trifluoromethyl)phenyl)hydrazinyl)pyrimidine (186 mg, 77%) as a brown oil: ¹H NMR (300 MHz, DMSO-d₆) δ 9.74 (bs, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 7.36 (m, 1H), 7.26 (bs, 5H), 7.01 (m, 3H), 5.14 (s, 2H); MS (ESI) m/z 379 (M+H)⁺, 377 (M−H)⁻.

B) A 25 mL vial was charged with 2-(benzyloxy)-5-fluoro-4-(2-(3-(trifluoromethyl)phenyl)hydrazinyl)pyrimidine (140 mg, 0.371 mmol), methanol (4.6 mL), titanium(III) chloride (12% in HCl, 5.0 μL, 0.0047 mmol), hydrogen bromide (33% in acetic acid, 4.0 μL, 0.022 mmol), and 35% hydrogen peroxide (64 μL, 0.744 mmol).* The resulting dark brown, homogeneous solution was agitated on an orbital shaker for 16 h at room temperature, after which a crystalline red solid was found to have formed. This solid was collected in a fritted funnel and was rinsed with a minimal amount of methanol to afford the title compound (54.5 mg, 39%) as a crystalline red solid: mp 123-125° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 9.07 (s, 1H), 8.22-8.37 (m, 2H), 8.12 (d, J=7.8 Hz, 1H), 7.94 (t, J=7.8 Hz, 1H), 7.46-7.53 (m, 2H), 7.30-7.44 (m, 3H), 5.43 (s, 2H); MS (ESI) ink 377 (M+H)⁺. *Drug, E.; Gozin, M. J. Am. Chem. Soc. 2007, 129, 13784-13785.

Preparation of N-(2-(allyloxy)-5-fluoropyrimidin-4-yl)-3-methylbenzohydrazide (959)

A) A 250 mL round bottom flask was charged with 2,4-dichloro-5-fluoropyrimidine (10.0 g, 59.9 mmol) and allyl alcohol (8.60 mL, 126 mmol). t-BuOK (1.0 M in t-BuOH, 132 mL, 132 mmol) was then added, and a significant exotherm was observed. The resulting mixture was allowed to stir at room temperature for 5 h. The crude reaction mixture was then diluted with EtOAc (300 mL) and washed with saturated aqueous NaCl solution (200 mL×2). The organic layer was dried over MgSO₄, filtered, and concentrated in a 500 mL round bottom flask. The crude mixture was diluted with ethanol (60 mL) and aqueous potassium hydroxide (2.0 M, 240 mL, 480 mmol), and the resulting biphasic mixture was heated at reflux for 18 h. After cooling to room temperature, the crude material was washed with Et₂O (200 mL×2) and then acidified with 2.0 M HCl (˜215 mL) to obtain a turbid solution with a pH of 3. This mixture was then diluted with saturated aqueous NaCl solution (200 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure to obtain 2-(allyloxy)-5-fluoropyrimidin-4-ol (6.47 g, 64%) as an off white solid: mp 138-141° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 13.00 (bs, 1H), 7.84 (d, J=3.7 Hz, 1H), 5.99 (m, 1H), 5.38 (m, 1H), 5.26 (m, 1H), 4.78 (m, 2H); MS (ESI) m/z 171 (M+H)⁺, 169 (M−H)⁻.

B) A 250 mL round bottom flask was charged with 2-(allyloxy)-5-fluoropyrimidin-4-ol 4.96 g, 29.2 mmol), N,N-dimethylaniline (5.45 mL, 43.0 mmol), phosphorous oxychloride (3.30 mL, 35.4 mmol), and acetonitrile (60 mL). The resulting solution was heated at 80° C. for 1 h. After cooling to room temperature, the crude material was diluted with Et₂O (300 mL) and was washed with 1.0 M aqueous NaH₂PO₄ (150 mL×2) and saturated aqueous NaCl (150 mL). The organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure to obtain 2-(allyloxy)-4-chloro-5-fluoropyrimidine contaminated with N,N-dimethylaniline (6.71 g, 72.5% pure, 89% calcd.) as a brown oil: ¹H NMR (300 MHz, DMSO-d₆) δ 8.78 (bs, 1H), 6.04 (m, 1H), 5.38 (d, J=16.8 Hz, 1H), 5.26 (d, J=10.3 Hz, 1H), 4.82 (dd, J=0.8, 5.3 Hz, 2H); MS (EI) m/z 187 (M+H)⁺.

C) A 25 mL vial was charged with 2-(allyloxy)-4-chloro-5-fluoropyrimidine (72.5% pure, 175 mg, 0.673 mmol), ethanol (4 mL), triethylamine (234 μL, 1.68 mmol), and hydrazine monohydrate (34 μL, 0.706 mmol). The resulting solution was then agitated on an orbital shaker at room temperature for 90 min. 3-Methylbenzoyl chloride (93 μL, 0.706 mmol) was then added, and the reaction was further agitated for 16 h. The crude reaction mixture was concentrated under reduced pressure, and then purified by flash column chromatography (EtOAc/hexane gradient) to afford the title compound (95.8 mg, 47%) as a pale yellow solid: mp 181-185° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 10.44 (bs, 1H), 9.75 (bs, 1H), 8.10 (d, J=3.5 Hz, 1H), 7.65-7.75 (m, 2H), 7.37-7.43 (m, 2H), 5.95 (m, 1H). 5.25 (m, 1H), 5.15 (m, 1H), 4.63 (m, 2H), 2.37 (s, 3H); MS (ESI) m/z 303 (M+H)⁺, 301 (M−H)⁻.

Preparation of (E)-5-Fluoro-4-(2-(4-methoxybenzylidene)hydrazinyl)pyrimidin-2(1H)-one (960)

A 25 mL vial was charged with 4-chloro-5-fluoropyrimidin-2(1H)-one (149 mg, 1.00 mmol),* ethanol (4 mL), triethylamine (148 μL, 1.06 mmol), and hydrazine monohydrate (52 μL, 1.07 mmol). The resulting yellow solution was agitated on an orbital shaker at room temperature for 3 h. 4-Methoxybenzaldehyde (123 μL, 1.01 mmol) was added, and the reaction mixture was heated at 50° C. for 16 h. After cooling to room temperature, the crude material was concentrated under reduced pressure and purified by reverse phase flash column chromatography to afford the title compound (49.3 mg, 19%) as a yellow solid: mp 202-208° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 10.60 (bs, 1H), 10.14 (s, 1H), 8.35 (s, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.38 (t, J=5.9 Hz, 1H), 6.97 (d, J=8.9 Hz, 2H), 3.80 (s, 3H); MS (ESI) ink 263 (M+H)⁺, 261 (M−H)⁻. *Driscoll, J. S.; Marquez, V. E.; Plowman, J.; Liu, P. S.; Kelley, J. A.; Barchi, J. J. J. Med. Chem. 1991, 34, 3280-3284. Yamashita, J.; Yamawaki, I; Ueda, S.; Yasumoto, M.; Unemi, N.; Hashimoto, S. Chem. Pharm. Bull. 1982, 30, 4258-4267.

Preparation of N-(2-(Benzyloxy)-5-fluoropyrimidin-4-yl)formamide (961)

A 10 mL Schlenk-type flask was charged with acetic anhydride (4.0 mL, 42 mmol), formic acid (2.0 mL, 53 mmol), and CH₂Cl₂ (20 mL), and was cooled to 0° C. under nitrogen. N,N-Dimethylpyridin-4-amine (275 mg, 2.25 mmol) was added, and the resulting solution was allowed to stir at room temperature for 10 min. Solid 2-(benzyloxy)-5-fluoropyrimidin-4-amine (495 mg, 2.26 mmol) was added, and the reaction stirred for another 21 h at room temperature. The crude reaction mixture was diluted with CH₂Cl₂ (50 mL) and washed with water (50 mL), saturated aqueous NaHCO₃ (50 mL), and water (50 mL). The organic solution was dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude material was then purified by flash column chromatography (EtOAc/hexane gradient) to afford the title compound (295.8 mg, 53%) as a white solid: mp 153-157° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 11.29 (bs, 1H), 9.34 (s, 1H), 8.48 (d, J=2.6 Hz, 1H), 7.29-7.46 (m, 5H), 5.32 (s, 2H); MS (ESI) m/z 248 (M+H)⁺, 246 (M−H)⁻.

Preparation of (4-amino-5-fluoropyrimidin-2-yloxy)methyl cyclopentanecarboxylate (962)

A) A 25 mL vial was charged with (E)-(4-((dimethylamino)methyleneamino)-5-fluoropyrimidin-2-yloxy)methyl cyclopentanecarboxylate (50.0 mg, 0.161 mmol), 1,4-dioxane (4 mL), and 1.0 M aqueous HCl (78 μL, 0.078 mmol) and was agitated on an orbital shaker for 5 h. The reaction was monitored by ultra performance liquid chromatography (UPLC) and determined to be incomplete, therefore an additional portion of 1.0 M aqueous HCl (78 μL, 0.078 mmol) was added. After 1 h, the reaction was quenched by the addition of 1.0 M aqueous NaHCO₃ (260 μL, 0.260 mmol) and concentrated under reduced pressure at 45° C. The dried residue was then extracted with EtOAc (5 mL×4), and concentrated to dryness under reduced pressure to obtain (5-fluoro-4-formamidopyrimidin-2-yloxy)methyl cyclopentanecarboxylate (43.5 mg, 95%) as a white solid: mp 76-79° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 11.38 (bs, 1H), 9.31 (d, J=5.7 Hz, 1H), 8.52 (d, J=2.6 Hz, 1H), 5.97 (s, 2H), 2.71-2.85 (m, 1H), 1.40-1.89 (m, 8H); MS (ESI) m/z 306 (M+Na)⁺, 282 (M−H)⁻.

B) A 25 mL vial was charged with (5-fluoro-4-formamidopyrimidin-2-yloxy)methyl cyclopentanecarboxylate (34.0 mg, 0.120 mmol), ethanol (1 mL), and hydrazine monohydrate (23.3 μL, 0.479 mmol). The resulting clear, colorless solution was then agitated on an orbital shaker at room temperature for 45 min. The crude reaction mixture was diluted with Et₂O (50 mL) and was washed with saturated aqueous NaCl solution (50 mL×2). The organic was dried over MgSO₄, filtered, and concentrated under reduced pressure to give the title compound (11.2 mg, 36%) as a white solid: mp 101-104° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.97 (d, J=3.4 Hz, 1H), 7.44 (bs, 1H), 5.86 (s, 2H), 2.69-2.83 (m, 1H), 1.42-1.91 (m, 8H); MS (ESI) m/z 256 (M+H)⁺, 254 (M−H)⁻.

Preparation of 2-Benzyloxy-5-fluoro-pyrimidin-4-yl-cyanamide (963)

To a mixture of sodium hydride (0.65 g, 0.27 mol) in dry THF (10 mL), was added 2-benzyloxy-5-fluoro-pyrimidin-4-yl amine (2.0 g, 0.009 mol) dissolved in THF (15 mL) at room temperature under nitrogen. The mixture was allowed to stir at room temperature for 30 min and then cyanogen bromide (1.45 g, 0.0136 mol) in THF (10 ml) was added to the reaction mixture and allowed stir at room temperature for 16 h. The reaction was diluted with sat. sodium bicarbonate (2×5 mL) and extracted with EtOAc (3×40 mL). The organic phase was dried over Na₂SO₄, and concentrated to a give a crude solid which was recrystallized by adding minimum quantity of ethyl acetate and hexane until solution became turbid. The solvent was decanted and a gummy brown solid was obtained. The gummy brown solid was rinsed with Et₂O (2×10 mL) and allowed to stand in Et₂O while stirring for 1 h, until a free solid formed. The resulting solid was filtered and dried to give the title compound (1.7 g, 77%) as a pale brown solid: mp 150-152 dec.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.80 (bs, 1H), 7.43 (m, 5H), 5.20 (s, 2H); MS (EI) m/z 245 (M)⁺.

Preparation of 1-[2-(Benzyloxy)-5-fluoropyrimidin-4-yl]-3-hydroxyguanidine (964)

To a solution of 2-benzyloxy-5-fluoro-pyrimidin-4-yl-cyanamide (2.9 g, 0.012 mol) in n-butanol (30 mL) in a 100 mL sealed tube was added hydroxylamine hydrochloride (4.1 g, 0.059 mol) and the solution was heated at 110° C. for 2 h. The reaction was cooled and checked by TLC and was determined to be complete. The solvent was removed in vacuo and the resulting mixture was diluted with water and extracted with EtOAc (3×30 mL). The organic layers were dried over Na₂SO₄, filtered, and evaporated. The crude product was purified further with reverse phase chromatography to yield the title compound (500 mg, 15% yield) as an off white solid; mp 150-152 dec.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.72 (s, 2H), 8.44 (d, J=2.6 Hz, 1H), 7.41 (m, J=13.8, 6.3 Hz, 5H), 5.34 (s, 2H); MS (EI) m/z 278 (M)⁺.

Biological Testing Protocols:

1. Evaluation of Fungicidal Activity: Leaf Blotch of Wheat (Mycosphaerella graminicola; Anamorph: Septoria tritici; Bayer Code SEPTTR):

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50% mineral soil/50% soil-less Metro mix until the first leaf was fully emerged, with 7-10 seedlings per pot. These plants were inoculated with an aqueous spore suspension of Septoria tritici either prior to or after fungicide treatments. After inoculation the plants were kept in 100% relative humidity (one day in a dark dew chamber followed by two to three days in a lighted dew chamber) to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse for disease to develop.

2. Evaluation of Fungicidal Activity: Leaf Spot of Sugar Beets (Cercospora beticola; Bayer Code CERCBE):

Sugar beets (variety HH-88) were grown in soil-less Metro mix in a greenhouse. The spores were harvested from moisturized infected leaf surface by washing whole leaves in water, and then filtered through two layers of cheesecloth. The young seedlings were inoculated with the spore suspension. The plants were kept in a dark dew room for 48 hrs, and then placed under a plastic hood in a greenhouse with a temperature of 26° C.

3. Evaluation of Fungicidal Activity: Leaf Spot of Peanut (Mycosphaerella arachidis; Bayer Code MYCOAR; Anamorph: Cercospora arachidicola):

Peanuts seedlings (variety Star) were grown in soil-less Metro mix. The spores were harvested from moisturized infected leaf surface by washing whole leaves in water, and then filtered through two layers of cheesecloth. The young seedlings were inoculated with the spore suspension. The plants were kept in a dark dew room for 48 hrs, and then placed under a plastic hood in a greenhouse with a temperature of 26° C.

4. Evaluation of Fungicidal Activity: Apple Scab (Venturia inaequalis; Bayer Code VENTIN):

Apple seedlings (McIntosh or Golden Delicious) were grown in Metro mix in a greenhouse. Fungal spores were collected from infected leaf tissue. Plants were inoculated with the spore suspension. Plants were placed in a dew room for 24 hours with 100% relative humidity and then transferred to a greenhouse with a temperature of 18° C. for disease to develop.

5. Evaluation of Fungicidal Activity: Black Sigatoka Disease of Banana (Mycosphaerella fijiensis; BAYER Code MYCOFI):

Efficacy against Mycosphaerella fijiensis was tested using newly emerged leaves of field grown banana plants. 20 ml of a diluted formulation of compound 1 of the required concentration were sprayed onto each test leaf over a delineated area of 20×20 cm. The leaves were subsequently allowed to become infected by natural inoculum, and were visually assessed for percent disease control ˜40-45 days later.

6. Evaluation of Fungicidal Activity as a Seed Treatment: Leaf Blotch of Wheat (Mycosphaerella graminicola; Anamorph: Septoria tritici; Bayer Code SEPTTR)

Seeds of wheat variety Yuma were treated with 10% SC formulation of compound 15 (Table 1) at rates of 120, 40, 13.3, 4.44, 1.48, and 0 g ai/100 kg seeds. Seeds (10 seeds/pot) were planted in 1 inch pot containing 50% mineral soil/50% soil-less Metro mix. 8-day old seedlings were inoculated with an aqueous spore suspension of Septoria tritici, and 8 pots of plants were inoculated for each fungicide rate. After inoculation, plants were kept in 100% relative humidity (one day in a dark dew chamber followed by two days in a lighted mist room) to allow establishment of infection. The plants were then transferred to a greenhouse for disease to develop. When infection levels on untreated plants reached 95 to 100%, disease severities on treated plants were assessed. At the lowest test rate of 1.48 g ai/100 kg seeds, compound 15 (Table 1) provided nearly complete control of SEPTTR (Table V), indicating that aminopyrimidine fungicides can efficiently deliver SEPTTR efficacy via seed treatment.

The following tables present the activity of typical compounds of the present disclosure when evaluated in these experiments. The effectiveness of the test compounds in controlling disease was determined by assessing the severity of disease on treated plants, then converting the severity to percent control based on the level of disease on untreated, inoculated plants.

In each case of Tables I-V the rating scale is as follows:

% Disease Control Rating  76-100 A 51-75 B 26-50 C  0-25 D Not Tested E

TABLE I Three day curative (3DC) and one day protectant (1DP) Activity of Compounds on SEPTTR at 25 and 100 ppm SEPTTR SEPTTR SETTTR SEPTTR Mass Mass 3DC 3DC 1DP 1DP Spec. Spec. Cmpd Structure 25 ppm 100 ppm 25 ppm 100 ppm Phys. App. MP (ES+) (ES−) GCMS 1

A A A A white solid 130-132 238 236 2

A A A A off-white powder 143-145 297, 298 3

A A A A oil product 250 4

A A A A off-white solid 163-165 247 5

A A A A White Solid 90-92 226 6

A A A A white solid 134-136 268 266 7

A A A A beige solid 125-126 350 348 8

A A A A clear yellow oil 352 350 9

A A A A white solid 103-105 514 10

A A A A white solid 129-131 358 356 11

A A A A clear oil 338 336 12

A A A A tan solid 87-90 417 415 13

D D C B white solid 109-111 374 372 14

A A A A clear colorless oil 310 308 15

A A A A White Solid 135-137 234 232 16

A A A A white solid 97-98 264 262 17

A A A A white solid 108-110 268 266 18

B B B A white solid 64-66 358 356 19

B A A A white solid 134-135 352 20

A A A A white powder 115-116 293 21

A A A A off white solid 102-103 319 22

A A A A white solid 169-171 281 279 23

A A A A off white solid 148-149 290 288 24

A A A A clear yellow oil 321 25

A A A A tan solid 240-243 183 26

A A A A white solid 124-126 258 27

A A A A white crystalline solid 136-138 289 28

A A A A white solid 124-125 325 29

B A A A white solid 139-140 270 268 30

B A B A white solid 88-90 346 344 31

D D D D off white solid 121-123.5 371 354 32

D A C A colorless oil 306 304 33

A A A A fluffy white solid 184-186 243 245 34

D D D D white solid 177-178 396 394 35

A A A A yellow solid 104-106 250 248 36

B A C A tan solid 75-78 420 418 37

A A A A white needles 150-151 339 337 38

D C C C White Solid 145-148 312 310 39

D D A A yellow solid 184 391 389 40

E E E E white solid 142-143 312 310 41

E E E E white solid 86-88 299 42

E E E E colorless oil 229 43

B B C B yellow glassy solid 126-130 327 44

B A D A off white solid 102-105 265 263 45

C C B A yellow solid 136-139 359 357 46

A A A A orange-white solid 220 218 47

E E E E off white solid 125-129 281 48

A A A A off-white solid 149-150 335 333 49

E E E E Pale yellow viscous liquid 377 50

C A C A pale yellow solid 123-125 259 51

E E E E Pale yellow solid 326 52

B B A A white solid 160-162 280 278 53

A A A A yellow glass 294 54

D D B A white solid 118-121 417 415 55

A A A A white solid 124 224 56

E E E E Pale yellow solid 338 57

A A A A white solid 122-124 282 58

A A A A white solid 170 (dec) 307 59

D C D D white solid 190-191 371 369 60

A A A A white solid 143 306 304 61

D D A A white solid 111-113 326 62

E E E E Off white solid 234 63

E E E E yellow oil 325 64

D C D D white solid 170-172 375 373 65

C B C B brown/orange solid 60-64 383 381 66

A A A A yellow solid 76-79 264 262 67

E E E E Pale yellow solid 459 68

D B D B WHITE SOLID 128-130 269 69

B A A A beige wax 300 298 70

C A C A white solid 94-97 312 71

A A A A 292 290 72

A A A A beige solid 155-156 265 263 73

E E E E Gummy liquid 310 74

D D B A white solid 245 243 75

A A C A off-white solid 164-166 435 433 76

C C C C black semi- solid 277 77

C A D A colorless oil 348 346 78

A A A A white solid 125-127 234 79

A A A A white solid 134-135 319 80

D B D D white solid 63-69* 272 81

D D D D off-white solid 187-189 361 359 82

D C C C orange oil 325 83

A A A A clear oil 278 84

E E E E Gummy liquid 262 85

A A C A yellow solid 151-156 403 401 86

D D C B white solid 368 366 87

D A B A yellow solid 154-155 379 377 88

C A C A clear colorless oil 282 280 89

A A A A tan solid 129-130 331 90

C B A A yellow solid 180-187 441 439 91

E E E E Gummy liquid 276 [M + Na] 92

E E E E Off white solid 381 93

A A A A white solid 122 274 272 94

A A A A off white solid 63-65 291 95

A A A A yellow solid 118-120 292 — 96

D D D D brown oil 334 97

D D D B white solid 104-107 348 345 98

D D D D white solid 168-169 389 387 99

D B D A white solid 74-77 244 100

D D D D white solid 163-164 254 252 101

D D B B white solid 127-129 338 102

D C D D dark brown solid 118-122 325 103

B A A A yellow solid 90-92 312 104

A A A A yellow solid 179-181 277 275 105

D D D D brown solid 143-148 288 285 106

D C D D yellow clear oil 240 238 107

A A A A white solid 280 278 108

A A A A white solid 123-124 321 109

E E E E white solid 188-192 276 274 110

E E E E Pale yellow solid 338 111

D D D D pale yellow oil 347 112

A A A A white solid 128-131 340.8 (Na+) 113

D C B A pale yellow gummy solid 266 114

D D D D white solid 133-135 389 307 115

A A A A yellow-white wax 271 116

D D D D white solid 162-164 377 375 117

C C C B yellow solid 173-178 391 389 118

E E E E Off white solid 338 119

B A C A white powder 122-123 351 349 120

A A A A off-white solid 173-174 270 268 121

B A B A clear pale yellow oil 372 370 122

C A D B white solid 107-108 325 323 123

C A D C clear yellow oil 356 354 124

E E E E Pale yellow liquid 294 125

D D C C yellow solid 175-180 509 507 126

A A A A brown oil 405 403 127

A A A A white solid 126 284 282 128

E E E E Off white solid 363 129

A A C A white solid 119-120 302 300 130

A A A A white solid 139-141 269 131

C A C B white crystals 133-134 263 132

A A A A beige solid 171-173 316 (M + Na) 133

B A B A white solid 120-123 248 134

B A D B 350 348 135

B A A A off-white solid 144-146 391 389 136

A A A A off-white solid 103-105 286 284 137

C A C A white solid 55-57 214 212 138

A A A A off white solid 111-116 254 252 139

D C C B white solid 106 356 354 140

A A A A white solid 120-125 317 141

B C D A beige solid 175-176 290 142

D D D D off-white solid 204-205 382 380 143

E E E E Off white solid 296 144

A A A A white solid 101 306 304 145

A A A A clear oil 260 146

A A A A white solid 295 147

C C D B off white solid 146.8-149.4 297 294 148

D D B B yellow solid 125-129 374 372 149

D B C A yellow oil 356 354 150

C A D A 322 320 151

C C D D yellow oil 417 415 152

C A C A white solid 157-161 341 339 153

A A A A white solid 144-145 275 273 154

A A A A white solid 158 335 155

A A B A white solid 94-96 330 156

A A A A white solid 128-130 318 316 157

C C C A yellow solid 170-175 379 377 158

A A A A white solid 91-93 342 340 159

C D D D off white solid 327 160

A A A A clear yellow oil 333 161

C A A A white solid 121.5-125 267 264 162

D D C A white solid 71-73 354 352 163

D D D D off-white solid 161-162 330 328 164

D B C B clear oil 360 165

E E E E Off white solid 397 166

A A A A brown semi- solid 391 167

D D D C white tacky solid 365 363 168

D C D C 334 169

D D B A off-white solid 154-155 393 391 170

D D D D off-white solid 169-171 353 351 171

A A A A off-white solid 85-87 248 246 172

D D D D white solid 77-78 188 186 173

D B B A white solid 141-147 322 174

A A A A 322 320 175

D D A A yellow solid 177-179 388 176

A A B A 362 177

A A A A white solid 119-120 342 178

A A A A white solid 153 264 262 179

A A A A white solid 155-156 276 274 180

D D D B white solid 163-165 417 415 181

A A A A white solid 203-205 259 257 182

A A A A white solid 160-161 307 305 183

D D D D white solid 175-177 378 376 184

B A A A white solid 147-148 289 185

A A A A pale yellow glass 268 186

D D B B fluffy white solid 172-173 323 321 187

D B D D light green solid 90-92 291 188

A A A A white solid 92-94 234 232 189

B A B A white solid 163-164 279 190

D D D D white solid 74-75 312 310 191

A A A A viscous yellow oil 354 352 192

B A A A white solid foam 193

A A A A yellow solid 120 326 324 194

A A A A white solid 154 274 272 195

C A B A light yellow solid 51-53 387 385 196

A A A A white solid 93-95 256 254 197

B A B A white solid 65-66 262 260 198

E E E E Pale yellow solid 441 199

B A D A 368 366 200

D D D C yellow solid 181-186 421 419 201

D D D D white solid 161-162 401 399 202

E E E E Pale yellow solid 380 203

D B D D white solid 159-161 — 303 204

E E E E Pale yellow solid 368 205

D B D D pale yellow oil 321 318 206

E E E E Off white solid 352 207

D D D C tan solid 142-147 298 296 208

D C D D white solid 196-198 371 369 209

A A A A white solid 84-85 275 210

A A A A white solid 121-123 256 254 211

A A A A off-white solid 173-174 326 324 212

A A A A off-white solid 122-124 346 344 213

A A A A White Solid 90-92 226 214

D D D D white solid 110-113 291 215

E E E E Off white solid 248 216

B A A A white solid 108-112 298 296 217

E E E E Pale yellow liquid 376 218

E E E E Pale yellow solid 473 219

D B B A off-white solid 141-143 262 260 220

A A A A 372 370 221

E E E E white solid 113-115 215 222

E E E E Pale yellow viscous liquid 423 223

A A A A white solid 132-134 236 234 224

D C C A white solid 184 347 345 225

E E E E 306 226

A A A A white glassy solid 68-77 370 227

A A A A white solid 56-57 324 322 228

B A C A light yellow solid 362 360 229

E E E E Off white solid 322 230

D D A A yellow solid 159-163 403 401 231

D D D D white solid 193-194 375 373 232

A A A A white solid 105-107 252 250 233

A A B A white solid 114-115 234

A A A A pale yellow solid 357 235

B A A A viscous yellow oil 345 342 236

A A A A white solid 111-113 238 237

D D D D white solid 62-65 240 238 238

D C D B clear colorless oil 515 513 239

B A A A white solid 165-166 403 401 240

D D D C white solid 86-87 268 266 241

A B A A white solid 164-165 365 242

E E E E Pale yellow solid 320 243

E E E E Pale yellow solid 429 244

D A D A pale yellow solid 138-142 332 329 245

B A B A white solid 145-148 254 252 246

E E D D white solid 157-158 254 252 247

A A A A off white solid 94-95 295 248

A A D A off white solid 102-104 304 249

C B C A off white solid 92-93 358 356 250

E E E E white solid 117-118 254 252 251

A A A A beige solid 120-122 300 252

D D C C white solid 132-135 253

B A C A yellow oil 263 261 254

E E E E Gummy liquid 268 255

E E E E Off white solid 200 256

D C D D white solid 83-84 184 182 257

B A B A white solid 90-91 296 294 258

C B B A off white solid 80-82 236 233 259

A A B A white solid 103-105 310 260

A A A A off white slid 95 (dec) 357 261

B A B A pale amber oil 340 262

A A B A white solid 101-105 263

E E E E Off white solid 270 M + Na 264

A A B A white solid 131-133 356 265

E E E E Yellow solid 344 266

D A A A white solid 137-138 391 389 267

D D D D white solid 104-105 172 170 268

C B D C white solid 126-127 247 269

D D D D pale green solid 91-94 265 237 270

D D D D white solid 111-112 239 271

B A A A white solid 119 306 304 272

A A A A clear yellow oil 349 273

A A B A 340 338 274

A A A A off white solid 84-86 319 275

A A A A beige solid 136 227 276

A A A A 322 320 277

E E E E 290 278

E E E E Off white solid 411 279

A A B A yellow gummy solid 316 280

A A A A 340 338 281

E E E E Pale yellow solid 427 282

C B D C dark brown solid 158-163 312 309 283

D C B A yellow solid 166-176 441 439 284

D D D D white solid 196-198 236 234 285

C C B A pale brown solid 118-120 331 329 286

B A A A off-white solid 121-123 248 246 287

A A A A white solid 115-116 363 361 288

D D D D white solid 188-190 401 399 289

A A A A white solid 128 254 290

E E E E Pale yellow solid 425 291

D C D D off-white solid 198-200 357 355 292

A A A A colorless oil 369 293

D D D D white solid 200-202 340 337 294

D A D A yellow oil 347 295

A A A A 366 296

D C D D white solid 235 233 297

E E E E Pale yellow liquid 368 298

A A A A 354 352 299

E E E E off white solid 83-88 562 300

A A A A white solid 106-107 250 248 301

B A C C tan solid 136-139 386 384 302

A A A A grey solid 105-107 386 303

B A C A thick oil 290 304

E E E E Yellow liquid 276 [M + Na] 305

E E E E white solid 292 290 306

C C D A brown solid 108-112 341 339 307

A A A A white solid 161-163 261 258 308

A A A A yellow solid 182-183 256 309

A A A A white solid 292 290 310

E E E E colorless oil 400 398 311

A A A A white solid 160-161 286 312

A A A A white solid 196-200 309 307 313

A A A A white solid 99-102 246 314

A A A A 317 315 315

A A B A white solid 64-65 202 200 316

A A A A yellow solid 138-140 303 317

C A B A pale amber oil 345 318

E E E E 314 319

E E E E Pale yellow viscous liquid 393 320

C C D D yellow solid 209 377 321

A A A A LIGHT YELLOW SOLID 112-114 244 322

D D D D yellow solid 235-237 267 265 323

A A A A white solid 153 248 246 324

D C A A yellow solid 185-189 409 407 325

A A A A off white solid 138-141 250 248 326

B A A A pale amber oil 333 327

B A B A pale amber oil 345 328

A A A A off-white solid 116-117 264 262 329

D D D D white solid 187-188 387 385 330

D C D A white solid 75-77 340 338 331

A A A A clear colorless oil 308 306 332

B C A A yellow-white solid 121-123 356 354 333

E E E E Gummy liquid 388 334

A A A A white solid 79-80 301 335

A A A A orange oil 282 336

E E E E Gummy liquid 262 337

C C C A white solid 191-192 208 206 338

A A A A white solid 102-103 349 339

C B D C white solid 63-65 264 262 340

C A D A yellow oil 294 291 341

A A A A white solid 129 268 266 342

A A A A off-white crystals 147-149 305 303 343

A A C A white solid 55-57 284 282 344

D C C C off white solid 117-121 363 361 345

A A A A white solid 154-156 276 346

A A A A clear oil 352 350 347

A A A A white solid 134-135 317 348

A A A A white solid 128-130 349

E E E E Pale yellow liquid 278 350

A A A A white solid 117 314 312 351

A A A A white solid 151 280 278 352

D D D D colorless liquid 310 307 353

D D D D white solid 68-72 335 333 354

C A B A clear pale yellow oil 370 368 355

A A A A white solid 150-152 330 356

C B C B orange oil 301 357

D B C C off white solid 173-177 313 311 358

C A D B brown solid 120-123 293 291 359

A C A A white solid 172-174 360 360

A A A A white solid 105-106 390 388 361

A A B A white solid 150-153 339 362

B A B A white solid 115-116 282 280 363

E E E E Pale yellow viscous liquid 441 364

A A A A white solid 114-115 342 340 365

A A A A tacky yellow glass 252 366

B A A A yellow solid 186-192 377 375 367

D D D D off white solid 94-97.5 341 368

A A A A tan solid 95-96 286 284 369

A A A A white solid 138-139 323 370

D D D D white solid 93-94 212 210 371

D D D D white solid 168-169 371 369 372

E E C A white solid 138-139 263 261 373

C B D D brown solid 44-50 313 310 374

A A B A clear pale yellow oil 282 280 375

C A D D yellow oil 322 320 376

D C D D lavender powder 214-216 363 361 377

B A A A pale amber oil 329 378

A A B A white solid 177-179 290 288 379

B A A A white solid 84-85 310 308 380

D A A A off white solid 73-76 343 381

A A A A light yellow solid 173-175 276 274 382

D A A A white solid 149-152 336 383

C D D D yellow solid 118-120 — 299 384

C A B A dark oil 241 239 385

A A A A ivory solid 104-105 292 290 386

A A A A white solid 124 264 262 387

A A A A orange oil 274 388

E E E E Pale yellow solid 384 389

A A A A light yellow solid 88.5-89.5 308.8 (Na+) 390

A A A A off white solid 96-100 236 234 391

C A B A off-white solid 132-135 346 344 392

A A A A off-white solid 210 393

C A C A clear oil 277 394

A A A A white solid 177-179 356 354 395

C B D D yellow oil 249 247 396

A A A A off-white solid 181-183 274 272 397

D D D D colorless oil 282 279 398

D C D D white solid 176-178 385 383 399

A A B A white solid 174 249 247 400

A A A A off-white solid 154-156 264 262 401

A A A A off-white solid 271 402

A A A A white solid 121-122 331 403

C A A A white solid 93-94 292 404

A A A A white solid 289 287 405

A A A A clear pale yellow oil 305 406

A A A A white solid 134-138 312 407

D D D D yellow oil 318 408

D A D A yellow solid 144-145 377 375 409

A A A A tan solid 210 410

B A B A white solid 114-115 336 411

C C A A white solid 138-142 400 398 412

D B D A colorless oil 344 342 413

A A A A white solid 245-247 234 232 414

E E E E white solid 125 (dec) 319 415

A A B A 384 382 416

D C D D 358 417

A A A A white solid 105-115 (dec) 253 418

A A A A brown oil 300 419

A A A A 336 334 420

A A A A white solid 93-94 255 421

A A A A pale amber oil 315 422

A A A A white solid 111-112 317 423

D D D D white solid 236 234 424

B A B A pale amber solid 93-100 347 425

A A A A white solid 95-99 372 426

E E E E Colourless liquid 324 427

A A A A yellow white solid 125-126 302 428

C A B B light yellow solid 309 307 429

A A A A beige solid 168-169 261 259 430

A A A A dark brown solid 128-130 235 233 431

A A A A clear yellow oil 238 432

E E E E Pale yellow solid 411 433

D D D D yellow solid 214 212 434

A A A A clear oil 338 435

B A A A white solid 115-117 324 322 436

A A A A white solid 115 241 437

D B D B brown solid 182-183 246 244 438

D D B A white solid 162-164 387 385 439

E E E E Yellow solid 298 [M + Na] 440

C D D D yellow solid 172-179 401 399 441

A A A A light yellow solid 61-62 278 276 442

A A A A fluffy off- white solid 195-196 297 293 443

C C A A yellow solid 173-177 387 385 444

A A A A white solid 121-123 336 445

A A B A brown oil 408 406 446

E E E E white solid 152-153 347 345 447

E E E E Pale yellow liquid 214 448

E E E E Pale yellow solid 364 449

E E E E Off white solid 489 450

A B A A white solid 155 294 292 451

D D D D white solid 158-160 263 261 452

A A A A white solid 108-109 326 324 453

B A A A light yellow glass 344 342 454

C D D A off white solid 153.5-157.9 337 334 455

C A B A white solid 101-103 268 266 456

D A B A yellow oil 377 457

B A B A LIGHT YELLOW SOLID 53-55 257 458

D D D B white tacky solid 358 356 459

A A B A 352 350 460

A A A A white solid 304 302 461

E E E E Gummy liquid 290 462

B C B A white solid 143-144 278 276 463

C B D B colorless oil 308 306 464

D C D D off-white solid 171-174 419 417 465

A A A A tan solid 155-157 271 269 466

D D D D light yellow glass 386 384 467

A A A A white solid 120-121 292.8 (Na+) 468

A A A A white powder 143-145 254 469

A A A A white solid 98-99 288 470

C C D D pale pink solid 154.4-157.2 342 340 471

E E E E Gummy liquid 282 472

A A A A yellow solid 58-61 266 264 473

C A C A fluffy white solid 123-124 253 251 474

A A A A clear oil 324 475

B A B A white solid 170-171 349 351 476

A A A A white solid 123-125 318 316 477

D B D D white solid 189-191 389 387 478

A A B A 372 370 479

B B A A yellow solid 143-150 488 480

D D D D pale yellow solid 150-154 324 322 481

A A A A white solid 169-174 (dec) 482

D C D D off white solid 111-115 312 309 483

A A A A clear yellow oil 307 484

A A A A yellow oil 323 485

D D D D white solid 206-207 357 355 486

C C D D ivory solid 188-189 302 300 487

D A D A white solid 153.8-157.1 268 266 488

D D D D white solid 191-192 238 236 489

A A D B white solid 122-123 182 180 490

A A A A 306 304 491

E E E E Pale yellow solid 411 492

D C D C pale brown solid 139-143 335 333 493

D D D C pale yellow solid 95-98 318 315 494

A A A A off white solid 77-78 293 495

E E E E Yellow solid 350 496

E E E E Pale yellow solid 463 497

D C B A white solid 123-124 352 350 498

A A A A white solid 56-58 296 294 499

E E E E 292 500

A A A A white solid 147-150 306 304 501

A A A A viscous semisolid 316 314 502

D D D D white solid 130-134 336 503

A A A A clear oil 341 339 504

D D D B off-white solid 165-166 412 410 505

E E E E Brown liquid 294 506

D D C A white solid 95-97 346 344 507

D A B A YELLOW GUMMY SOLID 382 508

A A A A tan solid 226 509

C D D D tan solid 72-77 220 218 510

B A B A white solid 150 262 260 511

C C B B yellow oil 271 512

D D D B off white solid 63-67 318 513

A A A A sticky solid 264 514

A A A A yellow oil 288 515

D D D A brown solid 123-129 363 361 516

A A A A clear pale yellow oil 303 301 517

A A A A white solid 125-127 243 518

A A A A tan oil 335 519

D D D D white solid 208-211 405 403 520

E E E E Pale yellow solid 308 521

E E E E Pale yellow solid 278 522

D D D C rust solid 188-189 246 244 523

A A A A white solid 127-130 356.8 (Na+) 524

D B D B white solid 100-101 264 262 525

A A A A yellow solid 154-160 427 425 526

D D D B yellow solid 216-218 404 527

D D B A yellow solid 178-182 459 457 528

D B A A tan solid 121-124 327 325 529

D D D D OFF WHITE SOLID 188-190 530

B A A A pale amber oil 321 531

A A A A 384 382 532

D C C B off white solid 157-162 343 341 533

D C B B white solid 120-123 331 329 534

D C D C white solid 147-148 335 333 535

D D D D white solid 182-183 387 385 536

C C D D white solid 171-172 319 317 537

A A A A off-white solid 112-113 292 290 538

B A C B pale biege solid 103-107 250 247 539

D D A A white solid 142-144 373 371 540

A A A A white solid 185 289 287 541

A A A A white solid 99-100 347 542

E E E E Off white solid 266 543

A A A A colorless oil 276 544

D D D C white solid 134-140 322 545

D B D C white solid 134-135 199 546

B D B B white solid 235-238 360 547

A A A A white solid 130-132 273 271 548

D D D D white solid 196-198 330 328 549

D D C D white solid 187-188 241 239 550

A A A A white solid 105-106 292 290 551

E E D C white solid 155-156 240 238 552

D A D A off-white solid 148-149 369 367 553

A A A A clear oil 334 332 554

C A C A white solid 123-124 260 258 555

D D D D white solid 203-205 (dec) 364 362 556

D A C A WHITE SOLID 100-103 323 557

D D C D white solid 208-210 343 341 558

C C A A yellow solid 167-171 373 371 559

A A B A PALE YELLOW SOLID 212 560

D A D C yellow solid 261 259 561

A A A A clear oil 349 562

D C D D yellow oil 333 331 563

E E E E Colourless liquid 290 564

C A B A white solid 109 248 246 565

E E E E White solid 445 566

D D D D white solid 158-159 323 321 567

C A C B clear yellow oil 388 386 568

A A B A off-white solid 125-126 339 337 569

B A A A white solid 90 320 318 570

A A A A off white solid 101-102 281 571

A A A A white solid 132-133 280 278 572

C B C A off-white solid 178-179 405 403 573

D D C B white solid 201-202 236 234 574

A A A A white solid 131 289 287 575

E E E E yellow oil 321 576

C A C A white solid 117-122 277 577

A A A A off-white solid 86-88 240 578

A A A A pale yellow solid 140-142 277 579

E E E E Pale yellow solid 262 580

D B B A white solid 185-187 256 581

A A A A white solid 120 268 266 582

A A A A off-white solid 162 290 288 583

A A D A white solid 108-109 249 247 584

D A D A off white solid 153-154 224 222 585

A A A A white solid 125 (dec) 323 586

D D D D colorless oil 320 587

C A D D white solid 200-201 363 361 588

D D D D white solid 86.3-89.8 335 589

D D D D white solid >200 294 292 590

A A A A white solid 154 268 266 591

E E E E Off white solid 282 592

A A A A yellow oil 260 593

E E D B white solid 134-135 240 238 594

D C D B white solid 104.4-107 356 354 595

D D C A off-white solid 160-161 391 389 596

A A A A off-white solid 105-107 305 302 597

A A A A clear oil 280 598

A A B A white solid 156-160 356 599

A A B A clear oil 359 357 600

A A A A clear oil 365 601

A A A A white solid 53-54 308 306 602

D D D B white solid 144 247 603

D D C A off white solid 173-176 374 372 604

A A A A off-white solid 106-108 #### #### 605

D A B A WHITE SOLID 64-67 350 606

E E E E 316 607

D C D D white solid 112-113 334 608

B A B A dark red oil 279 262 609

A A A A white solid 112 280 278 610

C B A A white solid 157-159 319 611

A A A A white solid 612

A A A A yellow solid 398 396 613

A A A A 368 366 614

A A A A white solid 75-76 310 308 615

A A C A YELLOW SOLID 58-60 237 616

A A A A white solid 149-151 287 617

A A A A clear oil 288 618

E E E E Off white solid 429 619

E E E E Gummy liquid 306 620

E E E E Pale yellow solid 350 621

E E E E Off white solid 266 622

E E E E Pale yellow liquid 296 623

B A A A white solid 112 280 278 624

B A B A LIGHT BROWN SOLID 128-130 310 625

D C D C white solid 114-115 202 626

A A A A white solid 130-131 317 627

E E E E Pale yellow solid 475 628

B A C A beige solid 101-103 227 629

D B D B light yellow solid 374 372 630

A A A A white solid 167-169 276 631

D D D D clear yellow oil 184 182 632

A A A A white solid 128-131 320 318 633

A A A A white solid 308 634

A A A A white solid 130-133 359 635

D A C A white solid 117-118 247 636

A A A A white solid 132-135 319 637

A A A A white solid 158-160 249 638

D B B A white solid 77-78 370 368 639

B A A A white solid 136-137 403 401 640

A A A A yellow white solid 218-220 258 641

E E E E Pale yellow liquid 276 642

E E E E white foam 61-65 410 (M + Na) 643

A A A A pasty off- white solid 644

A A A A white solid 164-166 255 645

D B C A white solid 117-118 264 262 646

A A B A white solid 185-187 298 296 647

A A A A white solid 89-90 290.8 (Na+) 648

A A A A white solid 132 344 342 649

D A D C LIGHT YELLOW SOLID 130-132 278 650

A A A A yellow solid 108 322 320 651

D B D D white solid 381 379 652

D A D B yellow oil 350 348 653

C A D D white solid 58-59 184 654

A A A A white solid 118-121 324 655

B C B A yellow solid 144-146 461 459 656

A A A A clear oil 334 657

E E E E Off white solid 459 658

D B D B YELLOW GUMMY SOLID 659

E E E E Pale yellow solid 477 660

C D A A white solid 160-161 661

E E E E Off white solid 280 662

C C D A yellow solid 176 409 407 663

A A A A yellow solid 123-124 323 664

D D D C OFF WHITE SOLID 125-127 356 665

E E E E Colourless liquid 242 666

E E E E Yellow solid 248 667

D A D A brown solid 108-111 357 355 668

A A C A 347 345 669

A A A A white solid 135-136 305 670

B A B A off-white solid 188-190 401 399 671

A A A A white solid 153-154 672

A A A A off-white solid 127-129 314 673

A A A A off-white solid 94-95 266 264 674

A A A A clear oil 366 364 675

A A A A light tan waxy solid 292 290 676

D D C A yellow oil 354 352 677

A A A A white solid 113-114 250 248 678

C A D A off-white crystals 128-129 321 319 679

A A A A off white solid 98-99 363 680

C C D D yellow solid 175-182 433 431 681

A A A A white solid 86-88 285 682

A A A A off-white solid 153-155 290 683

E E E E Colourless liquid 236 [M + Na] 684

A A A A white solid 94-95 335 685

D D D A yellow solid 175-183 433 431 686

E E E E white solid 160-161 262 260 687

D D C A yellow solid 122 338 336 688

A A A A white solid 93-95 289 689

A A A A white solid 126-128 254 252 690

A A B A 379 377 691

B A B A yellow solid 162 262 260 692

A A A A clear yellow oil 305 693

A A A A white solid 127-130 292 290 694

D C D C white solid 181-183 451 449 695

D C D A WHITE SOLID 100-102 256 696

B A A A off-white solid 98-102 276 274 697

C C D D LIGHT YELLOW SOLID 393 698

A A A A white solid 117 314 312 699

B A A A tannish solid 222 700

C A D B tan solid 185-187 375 373 701

D A D A pale yellow solid 138-142 332 329 702

A A A A clear oil 382 380 703

D D D C white solid 116-117 435 433 704

A A A A white solid 76-77 347 705

B A A A white solid 117-119 288 286 706

D B D A light yellow solid 163-165 346 344 707

A A A A orange solid 156 299 297 708

A A A A white solid 89-90 292 290 709

D B D A clear colorless oil 388 386 710

B A B A colorless oil 262 260 711

C A B A white solid 138-139 379 377 712

E E E E Off white solid 415 713

B A A A brown solid 95-98 238 714

A A A A yellow oil 294 292 715

D D C B white solid 198-201 251 249 716

A A A A yellow solid 93 326 324 717

A A B A 338 718

C C C A pale yellow solid 135-139 356 353 719

E E D B white solid 103-104 300 298 720

A A A A white solid 115 299 721

E E E E 370 368 722

D C D D light yellow solid 58-59 184 182 723

E E E E Pale yellow solid 400 724

D D D C white solid 170-171 335 333 725

A A A A yellow solid 146-147 346 344 726

A A A A white solid 109-110 305 727

A A A A clear yellow oil 307 305 728

E E E E Brown liquid 228 729

B B B C light yellow solid 178-180 307 730

A A A A clear yellow oil 279 731

D D D D white solid 84-85 200 198 732

B A A A pale amber oil 362 733

A A A A white solid 96-98 234 232 734

A A A A White solid 110-111 250 248 735

A A A A white solid 378 736

D D D D white solid 370 368 737

D D D D YELLOW SOLID 361 738

E E E E Pale yellow solid 334 739

A A A A white solid 87-88 295 293 740

E E D D yellow oil 242 240 741

A A C A clear colorless oil 280 278 742

E E E E Pale yellow solid 284 [M + Na] 743

A A A A yellow solid 93 320 744

A A A A tan oil 335 745

A A A A WHITE SOLID 158-160 224 746

D A D D orange solid 106-108 168 166 747

B A D A tan oil — 196 748

E E D D white solid 112-113 250 248 749

A A A A 324 322 750

C B C A 328 751

C A B A pale amber oil 319 752

A A A A colorless oil 308 306 753

A A A A clear pale yellow oil 278 276 754

D C D D colorless oil 336 333 755

D D C C pale yellow oil 331 756

C D D D white solid 199-200 348 346 757

A A A A light yellow needles 127-129 299 297 758

C B C A yellow solid 163-170 459 457 759

C A B A yellow oil 330 328 760

E E E E Off white solid 356 761

E E E E Brown liquid 306 762

A A A A white solid 61-62 352 350 763

A A A A off-white solid 221 764

D D D D white solid 145-146 278 276 765

D D D C white solid 44-49 335 333 766

D C D B dark brown solid 132-140 325 323 767

A A A A white solid 110 (dec) 319 768

D C D C white solid 183-184 249 247 769

D A B A off-white solid 150-152 421 419 770

A A A A yellow oil 306 771

A A A A 386 384 772

A A A A yellow solid 180-181 255 773

D D C A white solid 132-134 368 366 774

D D D D LIGHT YELLOW SOLID 339 775

D D D D white solid 77-80 310 307 776

D D D D white solid 157-158 311 309 777

D C D D white solid 404 402 778

A A A A white solid 146-147 387 385 779

A A A A white solid 118-120 201 780

A A A A white solid 107-108 268 266 781

D C D B light yellow solid 160-162 398 396 782

C A D C 375 373 783

A A A A off-white solid 51-54 278 276 784

D D D D white solid 112-115 250 785

A A A A white solid 163-164 340 786

E E E E Pale yellow semi solid 370 787

A A A A white solid 171 286 284 788

A A A A white solid 59-60 285 789

A A A A white solid 134-141 353 790

A A A A clear oil 304 791

E E E E clear oil 365 792

C B A A white solid 123-125 338 336 793

D D D D off white solid 158-166 323 321 794

A A A A white solid 108 266 795

A A A A white solid 124-125 335 796

A A A A white solid 149 286 284 797

C A B A off-white solid 167-168 417 415 798

A A A A clear oil 358 799

D D D D white solid 200-202 363 361 800

A A A A tan solid 238 801

E E E E Off white solid 338 802

D D D D white solid 98-99 230 228

TABLE II 1 DP Activity of Compounds on SEPTTR at 50 and 200 ppm SEPTTR SEPTTR Mass Mass 1DP 1DP Phys. Spec. Spec. Cmpd Structure 50 ppm 200 ppm App. MP (ES+) (ES−) GCMS 803

D B 320 804

C B 360 805

B A 342 806

E A 384 807

E A 294 808

A A 350 809

B A 346 810

E A 350 811

A A 412 812

E A 290 813

A A 412 814

E A 384 815

A A white solid 115-118 354 352 816

A A 378 817

C A 318 818

D D 317 819

E A off white solid 328 820

C A 362 821

E A 290 822

C A 332 823

E A 290 824

A A 346 825

B A 364 826

E A 328 827

D C 314 828

D D 304 829

C A 428 830

D D 308 831

B A 322 832

D D white solid 167-169 238 236 833

C B 318 834

E A 296 835

E A 384 836

B A 304 837

D D 316 838

E A 384 839

E A 360 840

B A 362 841

B A 346 842

A A 388 843

C A 330 844

A A 357 845

A A 296 846

D C white solid 108-110 226 224 847

A E white solid 155-157 288 286 848

D D white solid 212 210 849

A A 316 850

D B yellow- white solid 189-191 144 851

A A 380 852

B A 278 853

D D white solid 112-114 158 854

B A 368 855

E A 344 856

E A off-white solid 221 857

B A 397 858

D C 335 859

A A 344 860

E A 400 861

D C 316 862

B A 338 863

A A 398 864

D C white solid 115-117 212 210 865

C A 358 866

D A 266 867

A A 334 868

B A 414 869

E A 346 870

E A 330 871

D C 338 872

C B 316 873

D D 335 874

D D 351 875

D A 316 876

D D 249 877

E A 330 878

A A yellow gummy solid 312 310 879

A A 380 880

D C 359 881

A A 274 882

A A 372 883

A A 398 884

A A orange oil 350 348 885

C B 334 886

A A 360 887

E A 294 888

D B 329 889

A A 397 890

E A 352 891

A A yellowish solid 221 892

B A 358 893

A A 362 894

D D 320 895

A A 294 896

E A 384 897

D B 308 898

D D 250 899

C A 306 900

B A 344 901

B A 363 902

E A 317 903

D A 336 904

D C 368 905

C B 336 906

E A 346 907

B A 398 908

A A 358 909

E A 328 910

E A 334 911

D D 358 912

E A 350 913

A A 329 914

D A 314 915

D D 337 916

A A 340 917

D B yellow- white solid 54-56 278 276 918

A A 362 919

E A 304 920

A A 359 921

A A 364 922

B C 330 923

E A 352 924

A A 362 925

D D 324 926

A A 338 927

B A 278 928

A A 372 929

B A 374 930

D A 342 931

E A 346 932

A A white solid 49-51 170 168 933

C B white solid 145-149 223 934

D C 340 935

C A 345 936

A A white solid 88-91 234 232 937

A A 330 938

E A 296 939

D A off-white solid 225 940

D D 274 941

D D 282 942

A A 414 943

B A 398 944

D D 280 945

A A 350 946

B A 334 947

A A white solid 144-146 330 328 948

D D 342 949

B A 330 950

D D 346 951

B A 342 952

E C 261 953

C A 412

TABLE III 1 DP Activity of Compounds on CERCBE, VENTIN, and MYCOFI CERCBE 1 DP CERCBE 1 DP VENTIN 1 DP VENTIN 1 DP MYCOFI 1 DP MYCOFI 1 DP Cmpd # 25 ppm 75 ppm 25 ppm 75 ppm 50 ppm 200 ppm  1 C C A A C B  3 E E D A E E  4 A A A A E E  5 E E A A E E  7 B B A A E E  9 D D A C E E  10 D D B A E E  11 D D A A E E  14 D D A A E E  15 E E A A E E  20 E E B A E E  23 D B B A E E  24 D D C A E E  35 E E A A E E  36 B B B A E E  46 E E A A E E  61 D D A B E E  68 B B B A E E  69 D C B A E E  79 D C C C E E 121 D D A C E E 122 C C A A E E 125 C C C A E E 135 C C B B E E 137 D D D A E E 141 D D D C E E 155 D D C D E E 158 D D B B E E 163 D D D C E E 164 D D C B E E 169 D D B C E E 180 D C C D E E 187 D C B C E E 189 C D B B E E 190 C C C C E E 207 D D D C E E 209 E E B A E E 211 D D C B E E 214 B B A A E E 221 C B D C E E 226 D C C A E E 233 D D D B E E 236 E E A A E E 248 D D D B E E 251 D B A A E E 260 A B A A E E 270 C C D C E E 271 C C C B E E 288 D C B C E E 311 C C C C E E 313 E E C B E E 316 B A A A E E 335 C A A A E E 337 B A B A E E 341 D D C D E E 342 C A A A E E 343 A A A B E E 345 E E B A E E 347 E E A C E E 352 D D D C E E 353 C C C A E E 356 B D B C E E 370 C C C C E E 373 D D D C E E 384 D D B D E E 410 C C C B E E 411 C C B B E E 418 D D B B E E 436 B C A A E E 452 D D D C E E 469 E E B A E E 481 C A A A E E 483 D D C A E E 488 D D C C E E 510 E E A A E E 524 D D B B E E 538 D D C B E E 554 D B A A E E 560 D C D A E E 569 C A A A E E 570 D C C A E E 582 B B A A E E 584 C C C C E E 593 C B A A E E 626 D D C A E E 630 D D B A E E 631 D D D C E E 635 C C C A E E 649 D D C C E E 651 C C D D E E 687 D D C B E E 694 C C C B E E 707 B C B B E E 710 D D C C E E 719 D C B B E E 720 D B B A E E 730 C C B B E E 732 C A C A E E 734 E E A A E E 739 D D C B E E 741 D D B A E E 764 C D C C E E 800 A A A A E E 804 D D D D E E 845 D D C C E E 849 C C A B E E 858 C C C D E E 860 D C C B E E 894 D D D C E E 933 C C D C E E 941 D D B C E E 952 D D D D E E

TABLE IV Three day curative (3DC) and one day protectant (1DP) Activity of Compounds on SEPTTR at 25 and 100 ppm SEPTTR SEPTTR SETTTR SETTTR Mass Mass 3DC 3DC 1DP 1DP Spec. Spec. Cmpd # MOLSTRUCTURE 25 ppm 100 ppm 25 ppm 25 ppm Appearance MP (ES+) (ES−) GCMS 954

C B C C white solid 247-250 276.96 955

D D D D white solid 120-122 386.3 956

D D D D off-white solid 221-223 267.9 957

C C D D White Solid 175-178 235 [M + 2] 232 958

C C D D red crystalline solid 123-125 377 959

D D D D pale yellow solid 181-185 303 301 960

D D D D yellow solid 202-208 263 261 961

A A A A white solid 153-157 248 246 962

A A A A white solid 101-104 256 254 963

C D D D Pale brown solid 150-152 dec. 245 964

D C D D Off white solid 150-152 dec. 278 965

C C C A tan solid 236-238 269 267 966

B B C B white solid 249-251 280.88 967

B B C C white solid 255-257 246.93 968

B B B B white solid 255-257 260.93 969

C B C C white solid 244-246 260.93 970

C C C B white solid 257-259 278.91 971

B A C C white solid 289-293 213 972

B B B A white solid 255-260 242.2 973

A B C C white solid 290-295 240.34 974

B C B A white solid 218-220 260 258 975

D D D D white solid 270-280 228.2 976

D D D D white solid 218-222 256.9 977

D A D B off white solid 234-235 252 250 978

D D D D white solid 244-245 272 270 979

D B D C white solid 243-234 240 238 980

D D D D white solid 230-240 213 981

D D D D white solid 224-230 250.89 982

A A A A Off white solid 60.4-63 332 983

A A A A Pale yellow solid 83.3-85.8 302 984

A A A A Off white solid 63.2-65.5 350 985

A A A A Off white solid 60.8-62.9 320 986

A A A A Off white solid 62.3-65.9 346 987

A A A A Off white solid 88.2-89.2 316 988

A A A A Pale yellow liquid NA 362 989

B A A A Pale yellow liquid NA 334 990

D D D D colorless oil 438 991

D D D D red oil 309 992

D C D D red oil 323 993

D B D C red solid 95-98 310 994

D D D C white solid 155-157 372.2 995

D D D C red solid 104-108 353 351 996

C B C B brown semi- solid 354 353 997

A A A A white solid 151-152 185 998

A A A A yellow solid 160-161 237 235 999

A A A A tan solid 168-169 275 1000

A A A A tan solid 183-184 279 1001

C A C A tan solid 181-182 347 345 1002

C B B A tan solid 185-186 354 352 1003

D B D D off-white solid 134-137 313.87 1004

D C D D white solid 152-155 341.94 1005

D D D D white solid 147-150 375.96 1006

D D D D white solid 129-131 324.2 1007

D D D D white solid 150-153 336.2 1008

D D D D white solid 134-136 295.9 1009

D D D D white solid 139-142 323.92 1010

D D D D white solid 150-153 357.92 1011

D D D D white solid 117-119 325.92 1012

D D D D white solid 120-122 353.97 1013

D D D D white solid 129-131 387.93 1014

D A D D red solid 114-118 361 1015

C A D D white solid 141-144 473.92 1016

B B D D off-white solid 158-160 (dec) 436.88 1017

D B D C pale yellow solid 109-115 289 1018

D D D D off white solid 88-92 240 239 1019

D D C C yellow solid 161-165 299 1020

C D D D off white solid 173-177 263 1021

C C D C white solid 132-135 241 239 1022

D C D D pale yellow solid 129-134 210 209 1023

D D D D yellow solid 196-202 236 235 1024

D D D D yellow solid 220-226 235 251 1025

C D D D yellow solid 104-108 294 1026

D C C C yellow solid 110-114 279 277 1027

D D D D white solid 162-166 456.1 1028

D D D D brown solid 115-119 329 327 1029

D D D D brown oil 379 377 1030

D D D D brown solid 143-147 403 403 1031

D D D D brown solid 126-130 253 251 1032

D D C C white solid 165-170 371 369 1033

D C D D off white solid 151-155 224 223 1034

D D D D off white solid 136-139 267 1035

D D D D brown solid 122-127 391 389 1036

D D D D brown oil 339 337 1037

D D D C brown oil 379 1038

D D D D brown solid 105-109 381 379 1039

D D D D red solid 119-124 343 341 1040

D D D D brown oil 361 359 1041

D D D D dark red solid 102-108 394 393 1042

D C D D red solid 112-118 347 345 1043

D D D D brown solid 110-116 400 397 1044

D D D D brown oil 386 384 1045

D D D D red solid 140-143 412 409 1046

D D D D purple oil 398 396 1047

C C D D brown solid 194-197 348 346 1048

D D D D red semi- solid 269 1049

C C D D red oil 305 303 1050

D C D D red solid 71-76 236 234 1051

C D D D yellow solid 197-201 287 285 1052

D D D D off white solid 120-123 264 263 1053

D D D D white semi- solid 239 238 1054

D D D D yellow oil 283 1055

D D D D off white solid 136-139 305 1056

C C D D pale yellow oil 187 1057

D D D D white solid 152-155 215 213 1058

D D D D white solid 80-85 174 172 1059

D C D D peach colored solid 115-120 185 183 1060

D D D D yellow solid 83-88 304 303 1061

D D C D yellow solid 118-123 327 325 1062

D D D D yellow solid 104-107 237 235 1063

D D D D brown solid 102-107 251 249 1064

D D D D brown solid 179-182 262 261 1065

D D D D pale brown oil 250 1066

D D D D pale yellow oil 174 172 1067

D D D D pale yellow oil 201 200 1068

D D D D White Solid 218-222 269 [M + 2] 266 1069

B B D D White Solid 200-203 249 [M + 2] 246 1070

D D C D White Solid 206-209 264 262 1071

C C D C White Solid 258-261 (dec) 303 [M + 2] 300 1072

D D D D off white solid 64-67 214 212 1073

D D C D peach colored solid 146-150 295 293 1074

D C D D brown solid 151-155 289 287 1075

D D D D brown oil 299 298 1076

D C D D beige solid 110 279 278 1077

D C D D brown solid 86-89 278 277 1078

C D D D brown solid 130-133 341 339 1079

D D D D yellow oil 275 272 1080

C C D D pale yellow solid 79-83 248 1081

D D D D off white solid 70-75 277 1082

D D D D white gum 250.1 248.1 1083

A A A A white solid 71-3 257 1084

A A A A white solid 62-4 311 1085

A A A A white solid 110-2 319 1086

D D D D brown oil 280 278 1087

D D D D tacky brown solid 276 274 1088

D D D C yellow oil 276 274 1089

C C D D red solid 114-118 351 1090

C C D D red solid 84-89 395 1091

C C D D brown solid 72-75 265 263 1092

D C D C off white solid 201-206 201 199 1093

D D D D brown oil 235 233 1094

C C D D brown solid 164-169 236 234 1095

D D D D off white solid 146-150 236 234 1096

D A D D off white solid 180-190 174 172 1097

D C D D dark red solid 110-113 301 1098

D D D D grey solid 209-213 255 253 1099

D D D D red oil 277 1100

C C D D red solid 68-71 339 337 1101

D D D D white solid 215-217 205.97 1102

C C D D white solid 216-218 297.88 1103

D D D D white solid 236-239 301.85 1104

D D D D off-white solid 203-205 231.91 1105

D D D D white solid 157-159 219.96 1106

D D D D off-white solid 209-211 369.89 1107

D D D D light tan solid 124-128 (dec) 363.95 1108

D D D D brown solid 248-251 327 323 1109

D D D D red solid 35-37 287 1110

D D D D red solid 92-95 267 267 1111

D D D D yellow solid 242-246 267 265 1112

D C D D brown solid 216-218 223 221 1113

A A A A white solid 116-121 270 1114

C A D D light yellow solid 173-175 239 237 1115

C A C A grey solid 188.1 186.2 1116

E E E E White solid 292.64 1117

E E E E White solid 277.57 1118

D D D D yellow solid 235-237 267 265 1119

A A A A white solid 106-110 244 242 1120

D D D D off white solid 158-160 277 275 1121

D D D D white solid 209-212 297 295 1122

D D D D white solid 194-197 379 377 1123

D D D D brown solid 143-146 267 265 1124

D D D D off white solid 164-171 290 288 1125

A A A A white solid 138-141 252 228 1126

A A A A white solid 76-79 306 282 1127

A A A A white solid 83-87 267 183 1128

D D D D off white solid 131-135 435 433 1129

D D D D white solid 83-89 269 267 1130

C D D D Pale brown solid 119-122 dec. 259 1131

A A A A pale yellow solid 190-191 213 211 1132

A A B B white solid 220-230 284 282

TABLE V Percent SEPTTR control delivered by compound 15 (Table 1) treated Yuma seeds Rate g/ % 100 kg Con- seeds Pot 1 Pot 2 Pot 3 Pot 4 Pot 5 Pot 6 Pot 7 Pot 8 trol 120  0  0  0  0  0  0  0  0 A  40  0  1  1  1  0  0  0  0 A  13.3  0  1  0  1  1  1  0  0 A  4.44  0  0  1  1  0  1  0  0 A  1.48  3  3  1  1  0  3  0  0 A  0 100 100 95 100 100 95 100 95 0 

1-5. (canceled)
 6. A compound of formula I

wherein R¹ is —N(R³)R⁴; R² is —OR²¹; R³ is: H; C₁-C₆ alkyl optionally substituted with 1- to 3 R⁵; C₂-C₆ alkenyl optionally substituted with 1-3 R⁵; a 5- or 6-membered heteroaromatic ring selected from the group consisting of furanyl, pyridinyl, pyridinyl-N-oxide, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, triazinyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl, each heteroaromatic ring being optionally substituted with 1-3 R³⁰; imidazole fused with an aromatic or heteroaromatic ring selected from the group consisting of benzene, oxazole, isoxazole, furan, thiazole, pyrimidine, pyridine, pyrrole, pyrazine, thiophene, each aromatic or heteroaromatic ring being optionally substituted with 1 to 3 R³⁰; benzo[1,3]dioxolyl; 3H-isobenzofuran-1-onyl; cyano; C₃-C₆ alkynyl optionally substituted with 1-3 R⁵; —C(═O)R⁶; —C(═O)OCH₂C(═O)R⁸; —C(═S)R⁶; —C(═S)NHR⁸; —C(═O)N(R⁸)R¹⁰; —OR⁷; —P(O)(OR¹⁵)₂; —S(O)₂R⁸; —SR⁸; —Si(R⁸)₃; —N(R⁹)R¹⁰; —N═C(R¹⁵)R¹⁶; —(CHR²²)_(m)R³⁷; —(CHR²⁴)OR²⁹; or —C(═NR¹⁶)SR¹⁶; or —C(═NR²⁷)NR¹³R²⁸; wherein m is an integer from 1-3; R⁴ is: H; hydroxyl; amino; C₁-C₆ alkyl, optionally substituted with 1-3 R⁵; —C(═O)R⁶; or —C(═O)N(R⁸)R¹⁰; alternatively R³ and R⁴ may be taken together to form: a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; ═C(R¹²)N(R¹³)R¹⁴; ═C(R¹³)(R¹⁴); ═C(R¹⁵)OR¹⁵; ═S(R³⁴)₂; or ═NR³⁵; R⁵ is independently halogen, C₁-C₆ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ haloalkylthio, amino, C₁-C₃ alkylamino, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylcarbonyl, C₂-C₆ alkylaminocarbonyl, —OH, N-methyl piperazine or C₃-C₆ trialkylsilyl; R⁶ is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl optionally substituted with 1-3 R³⁰, C₁-C₅ haloalkyl, C₁-C₅ alkoxy, C₁-C₅ haloalkoxy C₂-C₆ alkoxycarbonyl, C₁-C₄ alkoxyalkoxy, C₂-C₆ alkylaminocarbonyl; 1-benzo[1,2,3]thiadiazol-7-yl, thiazolyl, benzyl, phenyl, phenoxy, or benzyloxy wherein the thiazolyl, benzyl, phenyl, phenoxy, or benzyloxy may be optionally substituted with 1-3 R²⁰, or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R⁷ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₅ halo alkyl, benzyl which may be optionally substituted with 1-5 R²⁰, —CHR¹⁸C(O)OR¹⁹, —(CHR²⁷)R²⁸, —Si(R⁸)₃, or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R⁸ is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, amino, C₁-C₆ alkylamino, C₂-C₆ dialkylamino, methylene-2-furanyl, —CHR¹⁵C(O)OR¹⁹, benzyl optionally substituted with 1-3 R³⁰, phenyl optionally substituted with 1-3 R³⁰, or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R⁹ is H, C₁-C₆ alkyl C₁-C₆ haloalkyl, —C(═O)R¹⁷, benzothiazoyl, quinazolinyl, or phenyl optionally substituted with 1-3 R²⁰, or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R¹⁰ is H or C₁-C₆ alkyl, C₁-C₆ haloalkyl, or phenyl optionally substituted with 1-3 R²⁰; R¹¹ is independently halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C_(r) C₆ alkylthio, C₁-C₆ haloalkylthio, amino, C₁-C₆ alkylamino, C₂-C₆ dialkylamino, C₂-C₆ alkoxycarbonyl, or C₂-C₆ alkylcarbonyl; R¹² is H or C₁-C₄ alkyl; R¹³ and R¹⁴ are independently H, cyano, —OH, C₁-C₄ alkyl, C₁-C₆ alkoxy, C₂-C₆, alkylcarbonyl, phenyl, or benzyl wherein the phenyl or benzyl may be optionally substituted with 1-3 R²⁰; alternatively R¹³ and R¹⁴ may be taken together to form: a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹, or 3,4-dihydro-1H-isoquinolin-2-yl; alternatively R¹² and R¹³ may be taken together to form: a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R¹⁵ is H or C₁-C₆ alkyl, C₂-C₆ alkenyl, 2-benzofuranyl, or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R¹⁶ is H, C₁-C₆ alkyl, or phenyl optionally substituted with 1-3 R²⁰; alternatively R¹⁵ and R¹⁶ may be taken together as —(CH₂)₄— or —(CH₂)₅—; R¹⁷ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, benzyl, phenyl, phenoxy, or benzyloxy wherein each ring may be optionally substituted with 1-3 R²⁰, a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R¹⁸ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R¹⁹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or benzyl; R²⁰ is independently halogen, cyano, nitro, amino, C₁-C₆ alkoxyalkoxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkoxyalkyl, C₂-C₆ haloalkoxyalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₃-C₆ alkynyl, C₃-C₆ haloalkynyl, hydroxyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyloxy, C₂-C₆ haloalkenyloxy, C₃-C₆ alkynyloxy, C₃-C₆ haloalkynyloxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₂-C₆ alkenylthio, C₂-C₆ haloalkenylthio, C₂-C₆ haloalkenylsulfonyl, C₃-C₆ alkynylthio, C₃-C₆ alkynylsulfonyl, C₃-C₆ haloalkynylsulfonyl, C₁-C₆ alkylamino, C₂-C₈ dialkylamino, C₃-C₈ dialkylaminocarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylcarbonyl, C₃-C₆ trialkylsilyl, 2-[(E)-methoxyimino]-N-methyl-acetamidyl, phenyl, benzyl, benzyloxy, phenoxy, or a 5- or 6-membered heteroaromatic ring wherein each phenyl, benzyl, benzyloxy, phenoxy, or 5- or 6-membered heteroaromatic ring may be optionally substituted with 1-3 substitutents independently selected from R³¹; R²¹ is: H; C₁-C₄ alkyl; C₁-C₆ haloalkyl; C₂-C₄ alkenyl; C₂-C₄ haloalkenyl; C₃-C₄ alkynyl; C₃-C₄ haloalkynyl; phenyl, naphthyl, or tetrahydroquinolinyl each optionally substituted with 1-3 R²⁰; —(CHR²²)_(m)R²³; —(CHR²⁴)_(m)C(O)OR²⁵; —(CHR²⁴)_(m)C(O)R²⁶; —(CHR²⁴)_(m)C(O)N(R²⁷)R²⁸; —(CHR²⁴)_(m)OR²⁹; —(CHR²⁴)_(m)SR²⁹; —(CHR²⁴)_(m)N(R²⁷)R²⁸; —C(═O)R³²; —N═C(R³²)(R³⁶); —NR²⁵C(═O)OR²⁵; —Si(R⁸)₃; —SO₂R³³; C₂-C₆ alkoxy carbonyl; C₂-C₆ alkylaminocarbonyl; C₂-C₆ alkyl carbonyl; sugars selected from the group consisting of beta-D-glucose-tetraacetate, rhamnose, fructose, and pentose; or a 5- or 6-membered heteroaromatic ring selected from the group consisting of furanyl, pyridinyl, pyridinyl-N-oxide, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, triazinyl, thiadiazolyl, oxazolyl, triazolyl or isoxazolyl wherein each 5- or 6-member heteroaromatic ring may be optionally substituted with 1-5 R²⁰; R²² is independently: H; halogen; cyano; nitro; C₁-C₆ alkyl; C₁-C₆ haloalkyl; phenyl or benzyl optionally substituted with 1-3 R²⁰; C₁-C₆ hydroxyalkyl; C₂-C₆ alkoxylalkyl; C₃-C₆ haloalkynyl; C₂-C₆ alkenyl; C₂-C₆ haloalkenyl; C₃-C₆ alkynyl; C₁-C₆ alkoxy; C₁-C₆ haloalkoxy; C₁-C₆ alkylthio; C₁-C₆ alkylamino; C₂-C₈ dialkylamino; C₃-C₆ cycloalkylamino; C₄-C₆ (alkyl)cycloalkylamino; C₂-C₆ alkylcarbonyl; C₂-C₆ alkoxycarbonyl; C₂-C₆ alkylaminocarbonyl; C₃-C₈ dialkylaminocarbonyl; C₃-C₆ trialkylsilyl; ring-fused heteroaromatic rings selected from the group consisting of benzothiophenyl, quinolinyl, isoquinolinyl, thieno[2,3-b]pyridyl, 1-methyl-1H-thieno[2,3-c]pyrazolyl, and benzoimidazolyl, wherein each of the rings may be further substituted with 1-3 R²⁰; or a 5- or 6-membered heteroaromatic ring selected from the group consisting of furanyl, pyridinyl, pyridinyl-N-oxide, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, triazinyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl and thienyl; R²³ is: H; halogen; C₁-C₆ alkyl; C₁-C₆ haloalkyl; C₂-C₆ dialkylamino; phenyl optionally substituted with 1-5 R²⁰; ring-fused heteroaromatic rings selected from the group consisting of benzothiophenyl, quinolinyl, isoquinolinyl, thieno[2,3-b]pyridyl, 1-methyl1H-thieno[2,3-c]pyrazolyl, benzofuranyl and benzoimidazolyl, 2,3-dihydrobenzofuran-2-yl, 4-methyl-4H-thieno[3,2-b]pyrrol-5-yl, 1-methyl-1H-indol-5-yl, imidazo[1,2-a]pyridin-2-yl, imidazo[2,1-b ]thiazol-6-yl, benzothiazol-2-yl, benzo[b]thiophen-7-yl, and 1-methyl-1H-indazol-3-yl, wherein each of the rings may be further substituted with 1-3 R²⁰; naphthyl; benzo[1,3]dioxolyl; pyrrolidinonyl; oxetanyl; C₁-C₆ alkylthio optionally substituted with 1-5 R²⁰; a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; or a 5- or 6-membered heteroaromatic ring selected from the group consisting of furanyl, pyridinyl, pyridinyl-N-oxide, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, triazinyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl, imidazolyl, thiophene-2-yl and thiophen-3-yl wherein each heteroaromatic ring may be optionally substituted with 1-3 R²⁰; R²⁴ is H, C₁-C₆ alkyl, C₁-C₆ alkoxy, benzyl, or phenyl wherein each of the benzyl or phenyl may be optionally substituted with 1-3 R²⁰; R²⁵ is H, C₁-C₆ alkyl, phenyl or benzyl optionally substituted with 1-3 R²⁰; R²⁶ is: H; C₁-C₆ alkyl; C₁-C₆ alkoxy; phenyl optionally substituted with 1-3 R²⁰; or a 5- or 6 membered heteroaromatic ring selected from the group consisting of furanyl, pyridinyl, pyridinyl-N-oxide, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, triazinyl, thiadiazolyl, oxazolyl, triazolyl and isoxazolyl; R²⁷ and R²⁸ are independently: H; benzyl or phenyl wherein each of the benzyl or phenyl may be optionally substituted with 1-3 R²⁰; or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R²⁹ is: H; C₁-C₆ alkoxyalkyl; benzyl, benzoyl, or phenyl wherein each of the benzyl, benzoyl, or phenyl may be optionally substituted with 1-3 R²⁰; or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R³⁰ is independently halogen, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkoxyalkyl, C₂-C₆ haloalkoxyalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₃-C₆ alkynyl, C₃-C₆ haloalkynyl, hydroxyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyloxy, C₂-C₆ haloalkenyloxy, C₃-C₆ alkynyloxy, C₃-C₆ haloalkynyloxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₂-C₆ alkenylthio, C₂-C₆ haloalkenylthio, C₂-C₆ haloalkenylsulfonyl, C₃-C₆ alkynylthio, C₃-C₆ alkynylsulfonyl, C₃-C₆ haloalkynylsulfonyl, C₁-C₆ alkylamino, C₂-C₈ dialkylamino, C₃-C₈ dialkylaminocarbonyl, C₃-C₆ trialkylsilyl, thiazolyl, phenyl, pyrimidinyl, or pyridyl, wherein the thiazolyl, phenyl, pyridyl, or pyrimidinyl may be optionally substituted with 1-3 R²⁰; R³¹ is independently halogen, cyano, nitro, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkoxyalkyl, C₂-C₆ haloalkoxyalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₃-C₆ alkynyl, C₃-C₆ haloalkynyl, hydroxyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyloxy, C₂-C₆ haloalkenyloxy, C₃-C₆ alkynyloxy, C₃-C₆ haloalkynyloxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₂-C₆ alkenylthio, C₂-C₆ haloalkenylthio, C₂-C₆ haloalkenylsulfonyl, C₃-C₆ alkynylthio, C₃-C₆ alkynylsulfonyl, C₃-C₆ haloalkynylsulfonyl, C₁-C₆ alkylamino, C₂-C₈ dialkylamino, C₃-C₈ dialkylaminocarbonyl, or C₃-C₆ trialkylsilyl; R³² is independently: C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkoxyalkyl, C₂-C₆ haloalkoxyalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₃-C₆ alkynyl, C₃-C₆ haloalkynyl, hydroxyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆ alkenyloxy, C₂-C₆ haloalkenyloxy, C₃-C₆ alkynyloxy, C₃-C₆ haloalkynyloxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₂-C₆ alkenylthio, C₂-C₆ haloalkenylthio, C₂-C₆ haloalkenylsulfonyl, C₃-C₆ alkynylthio, C₃-C₆ alkynylsulfonyl, C₃-C₆ haloalkynylsulfonyl, C₁-C₆ alkylamino, C₂-C₈ dialkylamino, C₃-C₈ dialkylaminocarbonyl, C₃-C₆ trialkylsilyl; phenyl wherein the phenyl ring may be optionally substituted with 1-3 R²⁰; or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R³³ is independently: C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl or thienyl optionally substituted with 1-3 R²⁰, or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R³⁴ is: C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkoxyalkyl, C₁-C₆ alkylamino; or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R³⁵ is: C₁-C₆ alkyl, C₂-C₆ alkylcarbonyl; or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R³⁶ is H, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy, benzyl, or phenyl wherein each of the benzyl, or phenyl may be optionally substituted with 1-3 R²⁰; alternatively R³² and R³⁶ may be taken together to form: a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; and R³⁷ is independently: H, halogen, or phenyl optionally substituted with 1-5 R²⁰; C₁-C₆ alkyl, C₁-C₆ haloalkyl, hydroxyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; wherein the compound of formula I must include at least one of the following substituents: R³ is —C(═NR²⁷)NR¹³R²⁸; R⁴ is hydroxyl or amino; R⁶ is C₂-C₆ alkenyl optionally substituted with 1-3 R³⁰; R⁷ is —(CHR²⁷)R²⁸, or —Si(R⁸)₃; R⁸ is methylene-2-furanyl, —CHR¹⁵C(O)OR¹⁹, or benzyl optionally substituted with 1-3 R³⁰; R⁹ is benzothiazoyl, quinazolinyl, or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R¹⁵ is C₂-C₆ alkenyl, 2-benzofuranyl, or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R¹⁷ is C₂-C₆ alkenyl, benzyl, or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹; R²⁹ is benzoyl.
 7. The compound of claim 6, wherein R³ and R⁴ are taken together to form a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹.
 8. The compound of claim 6, wherein R³ is —C(═NR²⁷)NR¹³R²⁸.
 9. The compound of claim 6, wherein R⁴ is hydroxyl or amino.
 10. The compound of claim 6, wherein R⁶ is C₂-C₆ alkenyl optionally substituted with 1-3 R³⁰.
 11. The compound of claim 6, wherein R⁷ is —(CHR²⁷)R²⁸, or —Si(R⁸)₃.
 12. The compound of claim 6, wherein R⁸ is methylene-2-furanyl, —CHR¹⁵C(O)OR¹⁹, or benzyl optionally substituted with 1-3 R³⁰.
 13. The compound of claim 6, wherein R⁹ is benzothiazoyl, quinazolinyl, or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹.
 14. The compound of claim 6, wherein R¹⁵ is C₂-C₆ alkenyl, 2-benzofuranyl, or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹.
 15. The compound of claim 6, wherein R¹⁷ is C₂-C₆ alkenyl, benzyl, or a 5- or 6-membered saturated or unsaturated ring containing 1-3 heteroatoms wherein each ring may be optionally substituted with 1-3 R¹¹.
 16. The compound of claim 1, wherein R²⁹ is benzoyl.
 17. A composition for the control of a fungal pathogen including the compound of claim 6 and a phytologically acceptable carrier material.
 18. The composition of claim 17 wherein the fungal pathogen is Apple Scab (Venturia inaequalis), Leaf Blotch of Wheat (Septoria tritici), Leaf spot of sugarbeets (Cercospora beticola), Leaf Spot of peanut (Cercospora arachidicola), and Black Sigatoka (Mycosphaerella fijiensis).
 19. A method for the control and prevention of fungal attack on a plant, the method including the steps of: applying a fungicidally effective amount of at least one of the compounds of claim 6 to at least one of the plant, an area adjacent to the plant, soil adapted to support growth of the plant, a root of the plant, foliage of the plant, and a seed adapted to produce the plant.
 20. The method of claim 19 wherein the fungal attach is caused by Leaf Blotch of Wheat (Septoria tritici). 